15-Deoxy-16-hydroxy-16-formyo or dimethoxy-methyl-prostane derivatives of the E and F series

ABSTRACT

The invention disclosed herein relates to pharmacologically active prostaglandins of the E and F series in which C-16 is substituted with hydroxyl and formyl or dimethoxymethyl as well as the pharmaceutically acceptable, non-toxic lower alkyl esters and salts thereof, and to the intermediates and processes for producing such compounds.

BACKGROUND OF THE INVENTION

(1) Field of the Invention

The present invention relates to 15-deoxy-16-hydroxy-16-formyl and 16-dimethoxymethyl prostaglandins, as well as the pharmaceutically acceptable, non-toxic lower alkyl esters and salts thereof, and to the intermediates and processes for producing such compounds.

(2) Description of the Prior Art

Prostaglandins have classically been described as chemically related 20 carbon chain hydroxy fatty acids having the basic skeleton of prostanoic acid: ##STR1##

The prostaglandins having a hydroxyl group at the C-11 position and a keto group at the C-9 position are known as the PGE series, and those having a hydroxyl group in place of the keto group are known as the PGF series and are further designated by an α or β suffix to indicate the configuration of the hydroxyl group at said position. The natural compounds are the α-hydroxy substituted compounds. They may contain different degrees of unsaturation in the molecule, particularly at C-5, C-13 and C-17, the unsaturation is also indicated by a suffix. Thus, for example, the PGF₁ and PGE₁ series refer to prostanoic acids having a trans olefin bond at the C-13 position, while the PGF₂ and PGE₂ series refer to prostadienoic acids having a cis-olefin bond at the C-5 position and a trans olefin bond at the C-13 position. For a review on prostaglandins and the definition of primary prostaglandins, see, for example, P. Ramwell, The Prostaglandins, 1, pp. 5-22 (1973).

The preparation of derivatives of prostanoic acid has become of great importance since the demonstration of the highly interesting range of biological and pharmacological activities of natural prostaglandins.

The great majority of these studies have focused on modification of the two side chains, or modifications of the substituents attached to the cyclopentane moiety [see for example U. Axen et al, Synthesis Vol. 1, John Wiley and Sons Inc., New York, New York. 1973 and P. H. Bently, Chem. Soc. Reviews, 2, 29 (1973)].

The synthesis of prostanglandin analogs possessing a 3-oxa- or 11-deoxy-3-thia moiety have been described, among others in U.S. Pat. Nos. 3,873,607; 3,950,406; Netherlands Pat. No. 7305222-Q; U.S. Pat. Nos. 3,944,593; U.S. Pat. No. 3,931,289; and U.S. Pat. No. 3,936,487.

The synthesis of several prostaglandin analogs wherein the hydroxyl group at C-15 has been removed and a hydroxyl group has been introduced at C-16 has appeard [see for example, U.S. Pat. No. 3,950,406; Prostaglandins, Vol. 10, 733 (1975); Tetrahedron Letters, No. 48, 4217 (1975).

Recently, reports have also appeared wherein the C-16 carbon bearing a hydroxyl group is substituted with a methyl group [see Pappo et al., Tetrahedron Letters, No. 4, 235 (1975); Collin et al., U.S. Pat. No. 3,965,143; and Belgium Patent No. 827,127].

Also, a patent has recently appeared wherein the C-16 carbon bearing the hydroxyl group is substituted with vinyl, methylvinyl, and cyclopropyl (U.S. Pat. No. 4,061,670).

Prostaglandins containing a formyl group have been reported at C-1 in the 15-hydroxy series in the U.S. Pat. No. 3,953,435 and at C-9 in the 11-deoxy-15-hydroxy series (See Advances in Prostaglandins and Thromboranes, page 486, Raven Press, New York, 1977). Ketals and/or acetals have also been reported in, among others, U.S. Pat. Nos. 3,915,994, 3,932,463, 3,962,218 and 4,088,775.

SUMMARY OF THE PRESENT INVENTION

In accordance with the present invention, we have prepared certain novel 15-deoxy-16-hydroxy-16-formyl and 16-dimethoxymethyl-prostaglandin analogs represented by the following formula: ##STR2## wherein Y is ##STR3## R₁ is selected from the group consisting of hydrogen and hydroxyl; R₂ is selected from the group consisting of hydrogen and C₁ -C₆ alkyl;

R₃ is selected from the group consisting of --CHO and --CH(OCH₃)₂.

R₄ is selected from the group consisting of hydrogen and C₁ -C₃ alkyl;

Z is selected from the group consisting of a divalent moiety of the formulae: --(CH₂)_(n) --, --(CH₂)_(m) OCH₂ --, --(CH₂)_(m) SCH₂ --, --CH₂ CH═CH(CH₂)_(p) --wherein n is 5 to 8, preferably 6, m is 3 to 6, preferably 4, and p is 2 to 5, preferably 3; the racemic mixture thereof; and when R₁ is hydrogen, the pharmacologically acceptable salts thereof.

The dotted lines shown in the above formula and in the formulas below indicate that the substituents are in the α-configuration, i.e., below the plane of the cyclopentane ring.

The double bond at C-13 in the compounds of the present invention has the same configuration as in natural prostaglandins of the PGE and PGF series, that is the trans configuration.

These novel compounds possess asymmetric centers and thus can be produced as racemic mixtures or as individual enantiomers. The racemic mixtures can be resolved if desired at appropriate stages by methods known to those skilled in the art, to obtain the respective individual enantiomers. It is to be understood that the racemic mixtures and the individual 8R-enantiomers are encompassed within the scope of the present invention.

When the compounds of the present invention are racemic mixtures, they are produced starting from racemates, while when the compounds of the invention are individual enantiomers the compounds are preferably obtained starting from the appropriate individual enantiomer.

Useful pharmacologically acceptable salts of the above formula, where R₁ is hydrogen, are those with pharmacologically acceptable metal cations, ammonium, amine cations or quaternary ammonium cations.

Preferred metal cations are those derived from the alkali metals, e.g., lithium, sodium and potassium, and from the alkaline earth metals, e.g., magnesium and calcium, although cationic forms of other metals, e.g. aluminum, zinc and iron, are within the scope of this invention.

Pharmacologically acceptable amine cations are those derived from primary, secondary or tertiary amines such as mono-, di- or trimethylamine, ethylamine, dibutylamine, triisopropylamine, N-methylhexylamine, decylamine, dodecylamine, allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, mono- or dibenzylamine, α- or β-phenyethylamine, ethylenediamine, and arylipatic amines containing up to and including 18 carbon atoms, as well as heterocyclic amines, e.g., piperidine, morpholine, pyrrolidine, piperazine and lower alkyl derivatives thereof, e.g. 1-methylpiperidine, 4-ethylmorpholine, 1-isopropylpyrrolidine, 2-methylpyrrolidine, 1,4-dimethylpiperazine, 2-methylpiperidine, and the like, as well as amines containing water-solubilizing or hydrophilic groups, e.g. mono-, di-, or triethanolamine, ethyldiethanolamine, N-butylethanolamine, 2-amino-1-butanol, 2-amino-2-ethyl-1,3-propanediol, 2-amino-2-methyl-1-propanol, tris-(hydroxymethyl)-aminomethane, N-phenylethanolamine, N-(p-tertamylphenyl)-diethanolamine, galactamine, N-methylglucamine, N-methylglucosamine, ephedrine, phenylephrine, epinephrine, procaine, and the like.

Examples of suitable pharmacologically acceptable quaternary ammonium cations are tetramethylammonium, tetraethylammonium, benzyltrimethylammonium, phenyltriethylammonium and the like.

DISCLOSURE

The novel compounds of this invention can be prepared by a 1,4-conjugate-addition procedure involving treatment of the ether blocked cyclopentenone (12) with a lithio-cuprate reagent such as (9), (10), or (11) prepared as illustrated in Flowsheets A, B, C and D.

Although Flowsheets A and B exemplify the use of a trimethylsilyloxy protecting group, any protecting groups which survive the conjugate addition reaction described by these tables and the examples of this application may be employed. Suitable protecting groups therefore include tri-(C₁ -C₄)-alkylsilyl, or other acid labile protecting groups such as tetrahydropryranyl, tetrahydrofuranyl or other acetals. Moreover, with reference to lithiocuprates of Flowsheet B (structures 8, 9, or 10) in addition to the lithiocuprates described, the lithiocuprates of structures 16 or 17 may also be employed.

In accordance with the procedure outlined in Flowsheet A, treatment of alkyl ester (1) with the sodium salt of dimethylsulfoxide, wherein R₄ is hydrogen, methyl, ethyl or propyl provides the keto sulfoxide (2). Treatment of the ketone (2) with iodine in methanol provides the ketoacetal (3) which upon treatment with propargylmagnesium bromide provides the hydroxy-alkyne (4) which is silylated to give the ether (5). The TMS ether (5) is heated with tri-n-butylstannane in the presence of azobisisobutyronitrile (AIBN) to afford the trans vinylstannane (6) which contains 10% to 20% of the corresponding cis vinylstannane (1).

Treatment of the vinylstannyl reagents (6 and 7) with n-butyl lithium at temperatures of -78° C. to -10° C. generates the vinyl lithium reagents (8). ##STR4##

In accordance with Flowsheet B, for the preparation of the asymmetrical lithio cuprate (9), a solution of one molar equivalent of copper (I)-1-alkyne, preferably copper (I)-1-pentyne in anhydrous tributylphosphine or HMPTA, preferably one to five molar equivalents, in ether is added to one molar equivalent of the aforementioned vinyl lithium solution cooled to about -78° C. After about one hour at this temperature, a molar equivalent of the requisite cyclopentenone (12) is added. After several hours at -30° C. to -70° C. the reaction mixture is quenched with aqueous ammonium chloride solution and the blocked product (13) is isolated in the usual manner.

It is also possible to effect conjugate 1,4-addition with the asymmetrical lithio cuprate (11) wherein R₄ is as previously defined derived from vinyl lithium and cuprous thiophenoxide. A solution of vinyl lithium (8) in THF at -78° C. is reacted with an equimolar amount of a reagent prepared by admixture, in ether at a temperature of 0° C. to -78° C. of equimolar amounts of cuprous thiopenoxide and copper (I) iodide tributylphosphonium complex. After about 30 minutes at this temperature, the lithio cuprate (11) is treated with the requisite cyclopentenone (12) as described hereinabove for the conjugate addition with 1-alkynyl lithio cuprate (9).

For the preparation of the symmetrical lithio cuprate (10) wherein R₄ is as previously defined one molar equivalent of copper (I) iodide tributylphosphine complex, dissolved in anhydrous ether, is added at about -78° C. to two molar equivalents of the aforementioned vinyl lithium (8) solution cooled to -78° C. After about one hour at this temperature, the lithio cuprate (10) is treated with the requisite cyclopentenone (12) as described hereinabove for the conjugate addition with the 1alkynyl lithio cuprate (9).

The procedures for conjugate addition involving organocopper reagents are well known in the art, see for example C. J. Sih, et al, J. Amer. Chem. Soc. 97, 865 (1975), which is incorporated by reference.

In the cases where R'₁ =trimethylsilyloxy in cyclopentenone (12) the conjugate addition is performed at -78° C. to -40° C. The reaction is quenched by addition of an ether solution of acetic acid. Removal of blocking groups is then carried out as described in the reference above to provide the product (14) wherein R₁, R₂, and R₄ are as hereinabove.

In order to hydrolyze the dimethoxymethyl group, more acidic conditions are required. The addition of a small amount of hydrochloric acid is necessary to provide (15), accompanied by the corresponding PGA derivative.

The introduction of a racemic β-chain possessing the 16-hydroxy-16-formyl and dimethoxymethyl groups provides a pair of prostaglandins epimeric at C-16. These two epimers may be separated into their upper (less polar) and lower (more polar) components by high-pressure liquid chromatography (HPLC) or by dry-column or preparative thin layer silica-gel chromatography.

If an optically active protected cyclopentenone such as (12) is utilized, then HPLC separation will provide the corresponding optically active nat. 9-oxo-11α,16α-dihydroxy-16-formyl and diethoxymethyl-PGE and nat. 9-oxo-11α,16β-dihydroxy-16-formyl-and dimethoxymethyl-PGE enantiomers.

All available evidence leads us to believe that the ##STR5## introduced by the cuprate process occupies a position trans to the 11-oxy function. Similarly, we are led to the conclusion that in the products (14) and (15) the two side-chains attached to C₈ and C₁₂ are trans to each other. However, we are not certain of this configurational relationship in the product as it is obtained directly from the cuprate process. These products may have the side-chains in a trans or cis-relationship or they may be a mixture containing both the trans- and cis-isomers. This is indicated in the nomenclature of the compounds involved by the designation ∥. In order to ensure a trans-relationship in (14) and (15) these products can be submitted to conditions known in the literature to equilibrate the cis-8-iso-PGE₁ to a mixture containing about 90% of the trans product. These conditions involve treatment with potassium acetate in aqueous methanol for 96 hours at room temperature.

The triloweralkylsilyloxy substituted lithio cuprate reagents of type (8) and the trialkylstannyl precursors are novel and useful compounds which are also embraced by this invention. They may be defined by generic formulae (16) and (17). ##STR6## wherein W is R-Sn where R is tri-(C₁ -C₆)-alkyl and preferably a tri-n-butyl group, or W is lithium; R₈ is tri-C₁ -C₄ alkylsilyl, preferably trimethylsilyl or other acid labile protecting groups such as tetrahydropyranyl, tetrahydrofuranyl or other acetals; R₉ is thiopenoxide, substituted thiophenoxide wherein the substituent may be C₁ -C₄ alkyl, C₁ -C₄ alkoxy, C₁ -C₃ dialkylamino or phenyl, or R₉ may be C₃ -C₄ alkyne or the identical vinyl moiety.

The cyclopentenones required for the preparation of the E₁, E₂, 3-oxa, and 11-deoxy-3-thia series have been described in the literature. The cyclopentenone for the preparation of 3-thia-11-hydroxy prostaglandins is described in Flowsheet D.

In accordance with Flowsheet D which is hereinbelow described, treatment of 2-furyl lithium (18) with a ω-chloroaldehyde (19) provides the chloroalcohol (20). Treatment of the chloroalcohol (20) with ethylmercaptoacetate furnishes the hydroxyester (21) which upon hydrolysis with sodium formate/formic acid provides the 3-hydroxy-cyclopentenone (22). Treatment of the cyclopentenone (22) with sulfuric acid provides the required 4-hydroxy-cyclopentenone (23) which after treatment with chlorotrimethylsilane provides the bissilylated cyclopentenone (24). ##STR7##

In accordance with Flowsheet E, when the 11-hydroxy or 11-oxy derivatives are treated with dilute acid, it is possible to effect elimination and the formation of the corresponding Δ¹⁰ derivatives (25) of the prostaglandin A-type. A preferred procedure involves treatment in tetrahydrofuran: water (2:1) solvent 0.5N in HCl for about 30 hours at ambient temperature. Under these conditions and tetrahydropyranyl or trialkylsilyl ester or ether will undergo hydrolysis. ##STR8##

The prostaglandin carboxylic acids of this invention can be readily converted to the various alkyl esters of this invention by treatment in the usual manner with the appropriate diazoalkane. The preparation of diazoalkanes by various procedures are well described in the art. See for example, C.D. Gutsche, Organic Reactions, VIII, 389 (1954). Certain of the esters of this invention can also be obtained directly by use of the appropriate cyclopentenone ester. The various esters can also be prepared by any of several procedures well-known in the art via an acid chloride (prior blocking of free alcohol groups with appropriate blocking groups such as trialkylsilyl, tetrahydropyranyl and the like) or mixed anhydrides and treatment of these intermediates with the appropriate alcohol. Mixed anhydrides can be obtained by treatment of the prostaglandin acid in a solvent such as dioxane and a temperature in the range of 0° C. to 15° C. with a molar equivalent of tri-alkylamine, preferably triethylamine, tributylamine and the like, and then a molar equivalent of isobutyl chlorocarbonate or the like. The resulting mixed anhydrides are then treated with the appropriate alcohol to give the derivatized product. [For a pertinent literature analogy see Prostaglandis, 4, 768 (1973).]

An alternative procedure involves treatment of the prostaglandin acid with a molar equivalent of the trialkyl amine in an excess of the appropriate alochol in an anhydrous solvent such as methylene chloride, molar equivalent of p-toluenesulfonyl chloride is then added (if necessary, a second molar equivalent can be added) and after stirring at ambient temperatures for about 15 minutes to one hour the product is worked-up in the usual manner. (For a pertinent literature analogy, see U.S. Pat. No. 3,821,279.) A third procedure involves the use of dicyclohexylcarbodiimide in the usual manner; for a pertinent literature analogy see German Offen. 2,365,205; Chem. Abst.,81, 120098 g (1974).

The esterified alcohol derivatives of this invention are also prepared in the usual manner by procedures well known in the art from the appropriate alkanoic acid anhydride or acid chloride.

When the compounds of this invention are prepared from racemic starting compounds, two racemates are obtained. In appropriate instances these racemates may be separated from each other by careful application of the usual chromatographic procedures. In the more difficult instances it may be necessary to apply high pressure liquid chromatography including recycling techniques. [See G. Fallick, American Laboratory, 19-27 (August 1973) as well as references cited therein. Additional information, concerning high speed liquid chromatography and the instruments necessary for its application, is available from Waters Associated Inc., Maple Street, Milford, Mass.]. ##STR9##

In accordance with Flowsheet F, treatment of a 16-dimethoxymethyl-prostaglandin of the E series (9-oxo) with a carbonyl reducing reagent such as sodium borohydride provides a mixture of the corresponding PGFα (9α-hydroxy) (26) and PGFβ (9β-hydroxy) (27) analogs. These two epimeric alcohols are readily separated by silica gel chromatography.

If one utilized the individuaal 16α-hydroxy or 16β-hydroxy E starting material, the isolated products after separation of the Fβproduct are the 9α, 16α-dihydroxy and 9α, 16β-dihydroxy derivatives, respectively.

Use of a steroselective reagent such as lithiumperhydro-9d-boraphenalylhydride [H. C. Brown and W. C. Dickason, J.A.C.S., 92, 709 (1970)] or lithium tri-sec-butylborohydride [H. C. Brown and S. Krishnamurthy, ibid, 94, 7159 (1972)] provides the PGFα product (26) as the selective species. Likewise, utilization of either the individual 16α- or 16β-hydroxy E compounds affords the corresponding 9α, 16α-di-hydroxy and 9α, 16β-dihydroxy prostaglandins of this invention.

After the reduction step has been completed, acid hydrolysis of the 16-dimethoxylmethyl-PGF compound will provide the 16-formyl derivative. ##STR10##

In accordance with Flowsheet G, when 11-hydroxy-16-dimethoxymethyl-PGF₂α congeners such as (28) are treated with an oxidizing reagent such as Jones Reagent, or pyridinium chlorochromate provides a selective oxidation to give the corresponding PGD derivative (9α-hydroxy-11-keto) (29) which is isolated after chromatographic purification.

If one utilized the individual 16α-hydroxy or 16β-hydroxy PGFα derivative of (28), then the corresponding 9α,16α dihydroxy-11-oxo and 9α,16β-dihydroxy-11-oxo-prostaglandins are isolated, respectively.

Hydrolysis of the 16-dimethoxymethyl-PGD congener with the mild acid treatment previously described provides the corresponding 16-formyl PGD derivate.

In the following formulae Z is as hereinabove defined.

The 4-hydroxycyclopentenone racemates may be resolved into their component enantiomers (31) and (32) wherein Z is as hereinabove defined by derivatizing the ketone function with a reagent having an optically active center. The resulting diastereoisomeric mixture can then be separated by fractional crystallization, or by chromatography, or by high speed liquid chromatography involving, if necessary, recycling techniques. Among the useful optically active ketone derivatizing reagents are 1-α-aminoxy-β-methylpentanoic acid hydrochloride (to give (30)), (R)-2-aminoxy-3,3-dimethylbutyric acid hydrochloride, and 4-α-methylbenzyl semicarbazide. After separation of the diastereomeric derivatives, reconstitution of the keto function provides the individual 4-hydroxycyclopentenone enantiomers (31) and (32). A useful procedure for the resolution of a 4-hydroxycylopentenone racemate via an oxime such as (30) is described in the art [R. Pappo, P. Collins and C. Jung, Tetrahedron Letters, 943 (1973)]. The resolution of the hydroxycyclopentenone (31) wherein Z is ##STR11## is described by Bruhn et al, Tetrahedron Letters, 235 (1976). The above references are herein incorporated by reference. ##STR12##

The novel compounds of the present invention have potential utility as hypotensive agents, anti-ulcer agents, agents for the treatment of gastric hypersecretion and gastric erosion, agents to provide protection against the ulcerogenic and other gastric difficulties associated with the use of various nonsteroidal anti-inflammatory agents (e.g., indomethacin, aspirin, and phenylbutazone), bronchodilators, anti-inflammatory agents, abortifacients, agents for the induction of labor, agents for the induction of menses, fertility-controlling agents, oestrus regulators for use in animal husbandry with cattle and other domestic animals and central nervous system regulatory agents. Certain of the novel compounds of this invention possess utility as intermediates for the preparation of the other novel compounds of this invention.

The novel compounds of this invention possess the pharmacological activity described below as associated with the appropriate above-described prostaglandin types.

The known PGE, PGF.sub.α, PGF.sub.β, PGA and PGD compounds are all potent in causing multiple biological responses even at low doses. For example, PGE₁, PGE₂, PGA₁ and PGA₂ are extremely potent in causing vasodepression and smooth muscle stimulation, and also are potent as antilipolytic agents. For example, the 11-deoxy-PGE compounds of this invention are selective in that they are at most relatively weak stimulants of smooth muscle. A further advantage of these novel compounds should be in their increased stabilities and lengthened shelf-lives.

Therefore, each of these novel prostaglandin analogs of this invention should be more useful than one of the corresponding above-mentioned known prostaglandins for at least one of the pharmacological purposes indicated below for the latter, either because it has a different and narrower spectrum of biological activity than the known prostaglandins, and therefore is more specific in its activity and causes smaller and fewer undesired side effects than the known prostaglandins, or because of its prolonged activity, fewer and smaller doses of the novel prostaglandin analog can frequently be used to attain the desired result.

Another advantage of the novel compounds of this invention, compared with the known prostaglandins, is that these novel compounds are administered effectively orally, sublingually, intravaginally, buccally, or rectally, in addition to the usual intravenous, instramuscular, or subcutaneous injection or infusion methods indicated above for the uses of the known prostaglandins. These qualities are advantageous because they facilitate maintaining uniform levels of these compounds in the body with fewer, shorter, or smaller doses, and make possible self-administration by the patient.

PGE₁, PGE₂, PGE₃, dihydro-PGE₁, PGF.sub.α, PGF.sub.β and PGA compounds, their esters and pharmacologically acceptable salts, are extremely potent in causing various biological responses. For that reason, these compounds are useful for pharmacological purposes. See, for example, Bergstrome, et al., Pharmacol. Rev., 20, 1 (1968), and references cited herein. A few of those biological responses are systemic arterial blood pressure lowering in the case of the PGA and compounds as measured, for example, in anesthetized (sodium phenobarbital) pentolinium-treated rats with indwelling aortic and right heart cannulas; pressor activity, similarly measured for the PGF compounds; stimulation of smooth muscle as shown for example, by tests on strips of guinea pig ileum, rabbit duodenum, or gerbil colon; potentiation of other smooth muscle stimulants; antilipolytic activity as shown by antagonism of epinephrine-induced mobilization of free fatty acids or inhibition of the spontaneous release of glycerol from isolated rat fat pads; inhibition of gastric secretion in the case of PGE compounds, as shown in dogs with secretion stimulated by food or histamine infusion; activity on the central nervous system; decrease of blood platelet adhesiveness in the case of PGE, as shown by platelet-to-glass adhesiveness, and inhibition of blood platelet aggregation and thrombus formation induced by various physical stimuli, e.g., arterial injury, and various biochemical stimuli, e.g., ADP, ATP, serotonin, thrombin, and collagen, and in the case of the PGE and PGA compounds, stimulation of epidermal proliferation and keratinization, as shown when they are applied in culture to embryonic chick and rat skin segments.

Because of these biological responses, these known prostaglandins are useful to study, prevent, control, or alleviate a wide variety of disease and undesirable physiological conditions in birds and mammals including humans, useful domestic animals, pets, and zoological specimens, and in laboratory animals, e.g., mice, rats, rabbits, and monkeys.

For example, these compounds are useful in mammals, including man, as nasal decongestants. For this purpose, the compounds are used in a dose range of about 10 mg to about 10 mg per ml of a pharmacologically suitable liquid vehicle or as an aerosol spray, both for topical application.

PGA, PGF.sub.β and PGE compounds are useful as hypotensive agents to reduce blood pressure in mammals including man. For this purpose, the PGF.sub.β compounds are administered by intravenous infusion at the rate of about 0.01 mg to about 40 mg per Kg of body weight per minute, or in a single dosage or multiple doses of about 25 mg to 2500 mg per Kg of body weight total per day. The PGE and PGA compounds are administered by intravenous infusion at the rate of about 0.01 to about 50 mg per Kg of body weight per minute, or in a single dose or multiple doses of about 25 to 2500 mg per Kg of body weight total per day.

The PGE, PGF.sub.α and PGF.sub.β compounds are useful in place of oxytocin to induce labor in pregnant female animals, including humans, cows, sheep and pigs, at or near term or in pregnant animals with intrauterine death of the fetus from about 20 weeks to term. For this purpose, the PGF compound is infused intravenously at a dose of 0.01 mg to 50 mg per Kg of body weight per minute until or near the termination of the second stage of labor, i.e., expulsion of the fetus. Similarly, the PGE compound is infused intravenously at a dose of 0.01 to 50 mg per Kg of body weight per minute until or near the expulsion of the fetus. These compounds are especially useful when the female is one or more weeks postmature and natural labor has not started, or 12 to 60 hours after the memberanes have ruptured and natural labor has not yet started.

The PGE, PGF.sub.α and PGF.sub.β compounds are useful for controlling the reproductive cycle in ovulating female mammals, including humans and other animals. For that purpose, PGF₂α, for example, is administered systemically at a dose level in the range of 0.01 mg to about 20 mg per Kg of body weight, advantageously during a span of time starting approximately at the time of ovulation and ending approximately at the time of menses or just prior to menses. Likewise, a PGE compound is administered in the same fashion at a dose level of 0.01 mg to about 50 mg per Kg of body weight. Additionally, expulsion of an embryo or fetus is accomplished by similar administration of the compound during the first third or the second third of the normal mammalian gestation period. Accordingly, such compounds are useful as abortifacients. They are also useful for induction of menses during approximately the first two weeks of a missed menstrual period and thus, are useful as contraceptive anti-fertility agents.

11α-hydroxy-PGE compounds are extremely potent in causing stimulation of smooth muscle, and are also highly active in potentiating other known smooth muscle stimulators, for example, oxytocic agents, e.g., oxytocin, and the various ergot alkaloids including derivatives and analogs thereof. Therefore PGE₂, for example, is useful in place of or in combination with less than usual amounts of these known smooth muscle stimulators for example, to relieve the symptoms of paralytic ileus, to control or prevent uterine bleeding after abortion or delivery, to aid in expulsion of the placenta, and during the puerperium. For the latter purpose, the PGE compound is administered by intravenous infusion immediately after abortion or delivery at a dose in the range about 0.01 to about 50 mg per Kg of body weight per minute until the desired effect is obtained. Subsequent doses are given by intravenous, subcutaneous, or intramuscular injection or infusion during puerperium in the range of 0.01 to 2 mg per Kg of body weight per day, the exact dose depending on the age, weight, and condition of the patient or animal.

The novel PGA, PGE and PGF.sub.β of this invention are also useful as bronchodilators for the treatment of asthma and chronic bronchitis. As such they may be conveniently administered by inhalation of aerosol sprays prepared in a dose range of about 10 μg to about 10 mg/ml of a pharmacologically suitable liquid vehicle. Relative to the natural prostaglandins, the PGA and PGE compounds in particular have the significant advantage of inducing prolonged effects.

The PGE and PGA compounds are also useful in mammals, including man and certain useful animals, e.g., dogs and pigs, to reduce and control excessive gastric secretion, thereby reducing or avoiding gastric erosion or gastrointestinal ulcer formation, and accelerating the healing of such ulcers already present in the gastrointestinal tract. For this purpose, the compounds are injected or infused intravenously, subcutaneously, or intramuscularly in an infusion dose range of about 0.1 mg to about 500 mg per Kg of body weight per minute, or in a total daily dose by injection or infusion in the range of about 0.1 to about 20 mg per Kg of body weight per day, the exact dose depending on the age, weight, and condition of the patient or animal, and on the frequency and route of administration. These compounds may also be useful in conjunction with various non-steroidal anti-inflammatory agents, such as aspirin, phenylbutazone, indomethacin and the like, to minimize the well-known ulcerogenic effects of the latter.

The PGE and PGA compounds also stimulate epidermal proliferation and keratinization, and in such a capacity are useful to promote and accelerate healing of skin which has been damaged, for example, by burns, wounds, abrasions or surgery. The PGA compounds are particularly useful in speeding the adherence and growth of skin autografts, especially small, deep (Davies) grafts which are intended to cover skinless areas by subsequent outward growth rather than initially, and in retarding rejection of homografts.

For these purposes, these compounds are preferably administered topically at or near the site where cell growth and keratin formation is desired, advantageously as an aerosol liquid or micronized powder spray, as an isotonic aqueous solution in the case of wet dressings, or as a lotion cream, or ointment in combination with the usual pharmaceutically acceptable dilutents. In some instances, when there is substantial fluid loss as in the case of extensive burns or skin loss due to other causes, systemic administration of PGE is advantageous, for example, by intravenous injection or infusion, separate or in combination with the usual infusions of blood, plasma, or substitutes thereof. Alternative routes of administration are subcutaneous or intramuscular near the site, oral, sublingual, buccal, rectal, or vaginal. The exact dose depends on such factors as the route of administration, and the age, weight, and condition of the subject. Illustrative of a wet dressing for topical application to second and/or third degree burns of skin area 5 to 25 square centimeters is the use of an isotonic aqueous solution containing one to 500 mg/ml of the PGA compound or several times that concentration of the PGE compound. Especially for topical use, these prostaglandins are useful in combination with antibiotics such as gentamycin, neomycin, polymyxin B, bacitracin, spectinomycin, and oxytetracycline; with other antibacterials such as mafenide hydrochloride, sulfadiazine, furazolium chloride, and nitrofurazone; and with corticoid steroids, such as hydrocortisone, prednisolone, methylprednisolone, and fluoro prednisolone; each of those being used in the combination at the usual concentration suitable for its use alone.

The PGA compounds and derivatives and salts thereof increase the flow of blood in the mammalian kidney, thereby increasing the volume and electrolyte content of the urine. For that reason, PGA compounds are useful in managing cases of renal disfunction, especially in cases of severely impaired renal blood flow, for example, the hepatorena syndrome and early kidney transplant rejection. In case of excessive or inappropriate antidiuretic hormone ADH vasopressin secretion, the diuretic effect of these compounds is even greater. In anephretic states, the vasopressin action of these compounds is especially useful.

The PGE compounds of this invention are also useful as topical vasodilators.

The PGE₁ compounds of this invention are useful whenever it is desired to inhibit platelet aggregation, to reduce the adhesive character of platelets, and to remove or prevent the formation of thrombi in mammals including man, rabbits, and rats. For example, these compounds are useful to treat and prevent myocardial infarcts and post-operative thrombosis. For these purposes, these compounds are administered systemically, e.g., intravenously, subcutaneously, intramuscularly, and in the form of sterile implants for prolonged action. For rapid response, especially in emergency situations, the intravenous route of administration is preferred. Doses in the range of about 0.005 to about 20 mg per Kg of body weight per day are used, the exact dose depending on the age, weight, and condition of the patient or animal, and on the frequency and route of administration.

It is well known that platelet aggregation inhibitors may be useful as anti-thrombotic drugs. Inhibition of platelet aggregation can be conveniently measured in vitro by monitoring changes in optical density and/or light transmission in platelet rich plasma upon addition of suitable aggregating agents such as adenosine diphosphate, epinephrine, thrombin or collagen. Alternatively, platelet aggregation can be measured in vitro using platelet rich plasma obtained at various time intervals from animals given inhibitors by an oral or parenteral route.

The PGE compounds of the present invention exhibit the ability to inhibit platelet aggregation in vitro when tested by the following procedure.

Human protein rich plasma is incubated with modified Tyrode's solution in a proportion of 40-50% human protein rich plasma. The test compounds are added at varying concentrations and after 5 minutes incubation, an aggregating agent such as adenosine diphosphate or collagen is added. The change in optical density (light transmission) is monitored by eye and inhbition is recorded as a (-) or lack of inhibition is recorded as a (+). Test compounds are considered active if they inhibit adenosine diphosphate or collagen induced aggregation at a concentration of 0.025 mg/ml or less within 5-10 minutes.

The PGE compounds of this invention also have bronchodilator activity as determined in a test using dogs anesthetized, artifically ventilated and submitted to a continuous respiratory spasm induced by pilocarpine.

Mongrel dogs of either sex weighing between 5 and 10 kg are used. They are premedicated with morphine HC1 by subcutaneous injection at 1.5 mg/Kg. An intravenous perfusion of 5% (W/V) chloralose is started 1/2 hour after the morphine injection in such a way that 60 mg/Kg are administered within 15 minutes. After completion, a continuous perfusion of 10 mg/Kg/hour is maintained throughout the experiment. The dogs are artificially ventilated by means of a Starling pump at a rate of 20 breaths/minute. The volume is adjusted according to the weight of the animal. [Kleinman and Radford, J. Appl. Physiol., 19, 360 (1964)]. All the measurements are made with the dogs positioned supine in a heated, V-shaped table. Curarzation is obtained by succinylcholine chloride using a starting injection of 3 mg/Kg lasting 3 minutes, followed by a continuous perfusion of 0.1 mg/Kg/minute.

The respiratory spasm is induced by a starting injection of 400 μg/Kg of pilocarpine HCl lasting 5 minutes. An increase or decrease in the dose of pilocarpine HCl may occur as a function of the observed effect on the airway's resistance. A 15 minute delay is observed before the start of a continuou perfusion of pilocarpine HCl at a dose of 4 μg/Kg/minute to maintain a constant spasm during the test.

A metallic cannula is inserted and fixed, after tracheotomy, into the upper part of the trachea. The two cephal veins and the two femoral veins are catheterized to inject the various agents. The femoral artery is catheterized to measure the systemic blood pressure. An esophageal balloon (11 cm×2.5 cm) is inserted into the lower third of the oesophagus to measure the endothoracic pressure. The measurement of a flow is made with a Fleish pneumotachograph connected to the tracheal tube.

The transpulmonary pressure is measured as follows. The tracheal cannula is equipped with a stainless steel axial tube (1.5 mm) which is closed at its distal end and projected 2.5 cm beyond the end of the cannula. Three holes with a diameter of one mm are pierced on this latter segment. This tube which is used to measure the tracheal pressure, is connected to one of the two chambers of a Sanborn 267 B/C differential transducer. The other chamber is connected to the esophageal ballon by means of a polyethylene catheter of the same length and characteristics as the balloon's.

The airflow is measured from the Fleish pneumotachograph by means of a Sanborn 270 differential transducer.

The tidal volume is obtained by electronic integration of the flow signal using an R.C. integrator.

The systemic and pulmonary blood pressures are gauged by means of a Sanborn 267 B/C or 1280B pressure transducer.

An electrocardiogram is taken in lead 2. Its use is to monitor a cardiac rate-meter.

All these parameters are recorded on a Sanborn polygraph. The transpulmonary pressure and the tidal volume are also displayed as rectangular coordinates on an oscilloscope.

The airway's resistance, expressed in cm of water/liter/second, is measured by subtracting from the electrical equivalent of the transpulmonary pressure, a voltage proportional to the flow so as to synchronize the pressure and volume signals on the oscilloscope [Mead and Whittenberger, J. Appl. Physiol., 5,779 (1953)].

The value of the pulmonary elastance, expressed in cm of water/liter, is obtained by means of the same principle, i.e., an electrical signal proportioned to the volume is subtracted from the transpulmonary pressure signal, in order to optimize the pressure-flow loop on the oscilloscope.

The details of this method are described by Lulling, et al. [Med. Pharmacol. Exp., 16, 481 (1967)].

    ______________________________________                                         KONZETT                                                                                         5-HT       Histamine                                          Compound         (ED.sub.50 g/kg)                                                                          (ED.sub.50 g/kg)                                   ______________________________________                                         dl-11α,16α/β-dihydroxy-9-oxo-                                                  1.25 × 10.sup.-3                                                                    8.89 × 10.sup.-6                             16-formyl-13-trans-prostenoic                                                  acid                                                                           ______________________________________                                    

REFERENCE EXAMPLE 1 1,1-Dimethoxy-2-hexanone

A mixture of 36.9 g of washed 50% sodium hydride dispersion (0.77 moles) and 600 ml. of dimethylsulfoxide is heated under argon at 65° C. for 2 hours. At 0° C. is added dropwise, 50 g. (0.38 moles) of ethyl valerate. The solution is stirred at room temperature for 2 hours, then diluted with 1400 ml. of water and 70 ml. of concentrated hydrochloric acid and 75 g. of sodium chloride is added. The mixture is extracted four times with chloroform and the solution is dried (magnesium sulfate charcoal). The solvent is removed. The residue is dissolved in 700 ml. of methanol. A 55.65 g. (0.22 moles) portion of iodine is added and the solution is refluxed 90 minutes. The solvent is removed, the residue is dissolved in chloroform and the solution is washed twice with water and once with saturated sodium thiosulfate. The solution is dried (magnesium sulfate charcoal). The solvent is removed and the residue is distilled twice. The fraction boiling at 64°-72° C., 5 mm. is collected to give 28.3 gm. of the title compound. [T. L. Moore, J. Org. Chem., 32, 786 (1967)].

REFERENCE EXAMPLE 2 4-Dimethoxymethyl-4-trimethylsiloxy-1-octyne

To a suspension of 5.31 g. (0.22 moles) of magnesium in 15 ml. of ether is added 100 mg. of mercuric chloride and 1.5 ml. of 1,2-dibromoethane. After the reaction begins, another 45 ml. of ether is added followed by the dropwise addition of a solution of 25 g. (0.16 moles) of 1,1-dimethoxy-2-hexanone and 27.3 g. (0.2 moles) of 85% propargyl bromide in 45 ml. of ether at a rate which maintains reflux. Midway through the addition 15 ml. of tetrahydrofuran is added. After complete addition of the solution, the mixture is refluxed for 40 minutes. The mixture is cooled to 0° C. and saturated ammonium chloride solution is added followed by magnesium sulfate. The mixture is filtered through Celite and the solvent is removed. The residue is dissolved in 53 ml. of dimethylformamide and at 0° C. is added 24.4 g. (0.36 moles) of imidazole and 21.19 g. (0.20 moles) of trimethylchlorosilane. After stirring at 25° C. for 70 minutes, the solution is poured into water and extracted with hexanes. The organic layer is dried over magnesium sulfate and the solvent is removed. Distillation (75°-95° C., 0.3 mm.) gives 17.4 g. of the title compound.

REFERENCE EXAMPLE 3 E-1-tri-n-Butylstannyl-4-dimethoxymethyl-4-trimethylsiloxy-1-octene

A mixture of 10.0 g. (36.7 mmoles) of 4-dimethoxymethyl-4-trimethylsiloxy-1-octyne, 12.82 g. (44 mmoles) of tri-n-butylstannyl hydride 100 mg. of azobisisobutyronitrile is heated to 140° C. under argon for 2 hours. The excess hydride is distilled off and the residue is purified by molecular distillation (bath temperature=170°-175° C., 0.2 mm.) to give 20.5 g. of the title compound.

REFERENCE EXAMPLE 4 11α,16-Dihydroxy-9-oxo-16-dimethoxymethyl-13-trans-prostenoic acid

To a solution of 10.2 g. (18.2 mmoles) of 1-tri-n-butylstannyl-4-dimethoxymethyl-4-trimethylsiloxy-1-octene in 10 ml. of tetrahydrofuran is added at -78° C. under argon with stirring 8.1 ml. of 2.0 M n-butyllithium in hexanes. The solution is maintained at -40° to -35° C. for 2 hours. The solution is cooled to -78° C. and a solution of 2.13 g. pentynyl copper and 6.55 g. of tri-n-butyl phosphine in 70 ml. of ether is added. After 45 minutes, a solution of 2-(6-carbotrimethylsiloxyhexyl)-4-trimethylsiloxycyclopent-2-en-1-one in 5 ml. of ether is added. After 0.5 hour at -45° C. and 0.5 hour at -45° to -20° C. the solution is quenched by adding saturated ammonium chloride solution. The mixture is stirred for 30 minutes and extracted with ether. The ether solution is washed with dilute hydrochloric acid. The ether is removed and the residue is stirred in a mixture of acetic acid:tetrahydrofuran:water (4:2:1) for 2 hours. The solvents are removed and the residue is chromatographed on a dry column of silica gel eluting with ethyl acetate:hexane (4:1) 1% acetic acid to give 2.07 g. of the title compound.

REFERENCE EXAMPLE 5 11α,16-Dihydroxy-9-oxo-16-formyl-13-trans-prostenoic acid

A solution of 1.5 g. of 11α,16-dihydroxy-9-oxo-16-dimethoxymethyl-13-trans-prostenoic acid in 40 ml. of acetic acid:tetrahydrofuran:water (4:2:1) containing 5 drops of 4 N hydrochloric acid is heated to 45° C. under argon for 2.5 hours. Another 5 drops of 4 N hydrochloric acid is added and the mixture is heated one hour. The mixture is diluted with toluene and the solvents are removed at reduced pressure. Toluene is added and removed twice. The residue is chromatographed on a dry column of silica gel eluting with ethyl acetate:hexane (4:1) containing 1% acetic acid to give 0.7 g. of the title compound.

REFERENCE EXAMPLE 6 PREPARATION AND SEPARATION OF 9α,11α,16-TRIHYDROXY-16-FORMYL-13-TRANS-PROSTENOIC ACID AND 9β,11α,16-TRIHYDROXY-16-FORMYL-13-TRANS-PROSTENOIC ACID.

To a stirred, ice-cold solution of 9-oxo-11α, 16-dihydroxy-16-dimethoxymethyl-13-trans-prostenoic acid in ethanol is added excess sodium borohydride in small portions during 1 minute. The mixture is stirred at 0° C. for 5 minutes and at ambient temperature for 1.5 hours. The bulk of the ethanol is evaporated in vacuo at room temperature and the residue is partitioned with cold, very dilute, hydrochloric acid and ethyl acetate. The organic phase is evaporated and washed with water and brine and dried over magnesium sulfate and concentrated in vacuo.

The residue is subjected to silica-gel chromatography to give: first eluted 9α, 11α, 16-trihydroxy-16-dimethoxymethyl-13-trans-prostenoic acid followed by 9β, 11α, 16-trihydroxy-16 -dimethoxymethyl-13-trans-prostenoic acid. Acid hydrolysis as described previously provides the individual 16-formyl derivatives 9α, 11α, 16-trihydroxy-16-formyl-13-trans-prostenoic acid and 9α, 11α, 16-trihydroxy-16-formyl-13-trans-prostenoic acid.

If one starts with the individual 16αor 16β-hydroxy isomer, then the corresponding products will also be 16αor 16β-hydroxy, respectively.

REFERENCE EXAMPLE 7 PREPARATION OF 9α, 11α,16-TRIHYDROXY-16-FORMYL-5-CIS, 13-TRANS-PROSTADIENOIC ACID

To a stirred solution solution of 9-oxo-11α, 16-Dihydroxy-16-dimethoxymethyl-5-cis,13-trans-prostadienoic Acid in tetrahydrofuran (THF) at -78° C. is added an excess of a 0.5 M solution of lithium perhydro-9-boraphenalyl hydride in THF. After 30 min. at -78°, the solution is warmed to 0° C. and treated with water. This mixture is partitioned with ether-potassium carbonate solutions. The aqueous phase is carefully acidified with hydrochloric acid, saturated with NaCl, and extracted with ethyl acetate. The organic extract is washed with brine, dried with magnesium sulfate, and concentrated in vacuo.

The residue is subjected to silica-gel dry column chromatography to provide 9α,11α,16-trihydroxy-16-dimethoxymethyl-5-cis, 13-trans prostadienoic acid. Mild hydrolysis (HOAC, THF, H₂₀ ; 4:2:1 and a few drops of 4 N HCl) provides 9α, 11α, 16-trihydroxy-16-formyl-5-cis, 13-trans-prostadienoic acid which may be separated into the individual 16α- and 16β-hydroxyl isomers by HPLC techniques.

REFERENCE EXAMPLE 8 PREPARATION OF 9-oxo-16-hydroxy-16-formyl-10, 13-trans-prostadienoic acid

9-oxo-11α,16-dihydroxy-16-formyl-13-trans-prostanoic acid is dissolved in a 1:1 tetrahydrofuran-water mixture containing 0.5 N HCl and allowed to stand at ambient temperature under argon for 72 hours. The solution is treated with brine and extracted with ether. The extract is washed with brine, dried over magnesium sulfate, and concentrated in vacuo to an oil. This residue is purified by dry column chromatography to give 9-oxo-16-hydroxy-16-formyl-10, 13-trans-prostadienoic acid. If one utilizes the individual 16αor 16βisomer, the product obtained is the 16αor 16β- epimer, respectively.

REFERENCES EXAMPLE 9 PREPARATION OF 9α,16-dihydroxy-11-oxo-16-formyl-13-trans-prostenoic acid

To a solution of 9α,11α, 16-trihydroxy-16-dimethoxymethyl-13-trans-prostenoic acid in acetone (12 ml/g.) at -35° C. is added, dropwise with stirring, one equivalent of Jones reagent (2.67 g CrO₃ and 2.3 ml of conc. H₂ SO₄ diluted to 10 ml with water). After 15 min isopropanol is added, followed by water. The mixture is poured into wateer, saturated with NaCl, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated in vacuo to an oil.

This oil is chromatographed on a dry column of silica-gel using ethyl acetate/heptane mixtures containing 1% acetic acid, to provide 9α,16-dihydroxy-11-oxo-16-dimethoxymethyl-13-trans-prostenoic acid. Mild acid hydrolysis (HOAC, THF, H₂ O, 4:2:1, few drops 4 N HCL) provides 9α,16-dihdyroxy-11-oxo-16-formyl-13-trans prostenoic acid.

If one starts with either of the individual 16α- or 16β -hydroxyl isomers, one isolates the 16α- or 16β-hydroxyl isomer, respectively.

REFERENCE EXAMPLE 10

Treatment of the ethyl esters of Table A by the procedure of Reference Example 1 provides the β-ketosulf-oxides of the table which are converted to the ketoacetals. Treatment of the ketoacetals of the table with propargyl magnesium bromide, provides the hydroxyalkyne that is protected as the TMS-alkyne of the table by the procedure of Reference Example 2. Hydrostannation by the procedure of Reference Example 3 provides the trans vinylstannanes of Table A.

                                      TABLE A                                      __________________________________________________________________________     Starting                   Trimethylsilyloxy                                   Ester    β-keto-sulfonide                                                                   ketoacetal                                                                              alkyne    trans vinyl stannane                      __________________________________________________________________________     ethyl butyrate                                                                          4-oxo-2-sulfinyl-                                                                       1,1-dimethoxy-2-                                                                        4-dimethoxymethyl-                                                                       1-trans-tri-n-butyl-                               heptane  pentanone                                                                               4-trimethylsilyloxy-                                                                     stannyl-4-dimethoxy-                                                 1-heptyne methyl-4-trimethyl-                                                            siloxy-1-heptene                          ethyl hexanoate                                                                         4-oxo-2-sulfinyl-                                                                       1,1-dimethoxy-2-                                                                        4-dimethoxymethyl-                                                                       1-trans-tri-n-butyl-                               nonane   heptanone                                                                               4-trimethylsilyloxy-                                                                     stannyl-4-dimethoxy-                                                 1-nonyne  methyl-4-trimethyl-                                                            siloxy-1-nonene                           ethyl heptanoate                                                                        4-oxo-2-sulfinyl-                                                                       1,1-dimethoxy-2-                                                                        4-dimethoxymethyl-                                                                       1-trans-tri-n-butyl-                               decene   octanone 4-trimethylsilyloxy-                                                                     stannyl-4-dimethoxy-                                                 1-decyne  methyl-4-trimethyl-                                                            siloxy-1-decene                           __________________________________________________________________________

The cyclopentenones of Table B which follow are employed in accordance with the conjugate addition reaction exemplified by Tables I and II which follow Table B.

Although in Tables I and II the product listed is the dl-racemic product when the cyclopentenone employed is an optically active cyclopentenone (such as structure 12), the application of HPLC, column or thin layer chromatography, will provide the individual nat. 16α and nat. 16β compounds.

                  TABLE B                                                          ______________________________________                                         CYCLOPENTENONES                                                                ______________________________________                                         A.        2-(5-Carbotrimethylsiloxypent-2-cis-enyl-4-                                    trimethylsiloxycyclopent-2-en-1-one                                  B.        2-(6-Carbotrimethylsiloxyhex-2-cis-enyl)-4-                                    trimethylsiloxycyclopent-2-en-1-one                                  C.        2-(7-Carbotrimethylsiloxyhept-2-cis-enyl-4-                                    trimethylsiloxycyclopent-2-en-1-one                                  D.        2-(5-Carbotrimethylsiloxypentyl)-4-                                            trimethylsiloxycyclopent-2-en-1-one                                  E.        2-(6-Carbotrimethylsiloxyhexyl)-4-                                             trimethylsiloxycyclopent-2-en-1-one                                  F.        2-(7-Carbotrimethylsiloxyheptyl)-4-                                            trimethylsiloxycyclopent-2-en-1-one                                  G.        2-(6-Cabotrimethylsiloxy-5-thia-hexyl)-4-                                      trimethylsiloxycyclopent-2-en-1-one                                  H.        2-(6-Carbotrimethylsiloxy-5-oxa-hexyl)-4-                                      trimethylsiloxycyclopent-2-en-1-one                                  I.        2-(6-Carbotrimethylsiloxyhex-2-cis-enyl)-4R-                                   trimethylsiloxycyclopent-2-en-1-one                                  J.        2-6(-Carbotrimethylsiloxyhexyl)-4R-                                            trimethylsiloxycyclopent-2-en-1-one                                  K.        2-(5-Carboethoxypent-2-cis-enyl)-                                              cyclopent-2-en-1-one                                                 L.        2-(6-Carboethoxyhex-2-cis-enyl)-                                               cyclopent-2-en-1-one                                                 M.        2-(7-Carboethoxyhept-2-cis-enyl)-                                              cyclopent-2-en-1-one                                                 N.        2-(5-Carboethoxypentyl)cyclopent-2-                                            en-1-one                                                             O.        2-(6-Carboethoxyhexyl)cyclopent-2-                                             en-1-one                                                             P.        2-(7-Carboethoxyheptyl)cyclopent-2-                                            en-1-one                                                             Q.        2-(6-Carboethoxy-5-thiahexyl)cyclopent-2-                                      en-1-one                                                             R.        2-(6-Carboethoxy-5-oxahexyl)cyclopent-2-                                       en-1-one                                                             ______________________________________                                    

TABLE I

Treatment of the appropriate cyclopentenones of Table B with the lithiocuprates generated from the vinylstannanes of Reference Example 3 and Reference Example 10 by the procedure of Reference Example 5 provides the 16-hydroxy-16-dimethoxymethyl derivatives that upon mild acid hydrolysis by the procedure of Reference Example 6 generates the 16-hydroxy-16-formyl PGE₁ derivatives of Examples 1-44 of Table I.

      EXAMPLE VINYL TIN CYCLOPENTENONE PRODUCT PROSTAGLANDIN OF THE PGE1      SERIES        1 1-trans-tri-n-butylstannyl-4-dimethoxymethyl- 2-(5-carbotrimethylsilo      xypentyl)- dl-11α,16-dihydroxy-9-oxo-16-formyl-  4-trimethylsiloxy-      1-heptene 4-trimethylsiloxycyclopent-2-en-1-one 20-nor-2-nor-13-trans      prostenoic acid 2 1-trans-tri-n-butylstannyl-4-dimethoxymethyl- 2-(5-carb      otrimethylsiloxypentyl)- dl-11α,16-dihydroxy-9-oxo-16-formyl-      4-trimethylsiloxy-1-octene 4-trimethylsiloxycyclopent-2-en-1-one      2-nor-13-trans prostenoic acid 3 1-trans-tri-n-butylstannyl-4-dimethoxyme      thyl- 2-(5-carbotrimethylsiloxypentyl)- dl-11α,16-dihydroxy-9-oxo-1      6-formyl-  4-trimethylsiloxy-1-nonene 4-trimethylsiloxycyclopent-2-en-1-o      ne 20-methyl-2-nor-13-trans prostenoic acid 4 1-trans-tri-n-butylstannyl-      4-dimethoxymethyl- 2-(5-carbotrimethylsiloxypentyl)- dl-11α,16-dihy      droxy-9-oxo-16-formyl-  4-trimethylsiloxy-1-decene 4-trimethylsiloxycyclo      pent-2-en-1-one 20-ethyl-2-nor-13-trans prostenoic acid 5 1-trans-tri-n-b      utylstannyl-4-dimethoxymethyl- 2-(6-carbotrimethylsiloxyhexyl)- dl-11.alp      ha.,16-dihydroxy-9-oxo-16-formyl-  4-trimethylsiloxy-1-heptene 4-trimethy      lsiloxycyclopent-2-en-1-one 20-nor-13-trans prostenoic acid 6 1-trans-tri      -n-butylstannyl-4-dimethoxymethyl- 2-(6-carbotrimethylsiloxyhexyl)-      dl-11α,16-dihydroxy-9-oxo-16-formyl-  4-trimethylsiloxy-1-octene      4-trimethylsiloxycyclopent-2-en-1-one 13-trans prostenoic acid 7      1-trans-tri-n-butylstannyl-4-dimethoxymethyl- 2-(6-carbotrimethylsiloxyhe      xyl)- dl-11α,16-dihydroxy-9-oxo-16-formyl-  4-trimethylsiloxy-1-non      ene 4-trimethylsiloxycyclopent-2-en-1-one 20-methyl-13-trans prostenoic      acid 8 1-trans-tri-n-butylstannyl-4-dimethoxymethyl- 2-(6-carbotrimethyls      iloxyhexyl)- dl-11α,16-dihydroxy-9-oxo-16-formyl-  4-trimethylsilox      y-1-decene 4-trimethylsiloxycyclopent-2-en-1-one 20-ethyl-13-trans      prostenoic acid 9 1-trans-tri-n-butylstannyl-4-dimethoxymethyl- 2-(7-carb      otrimethylsiloxyhexyl)- dl-11α,16-dihydroxy-9-oxo-16-formyl-      4-trimethylsiloxy-1-heptene 4-trimethylsiloxycyclopent-2-en-1-one      20-nor-2-homo-13-trans prostenoic acid 10 1-trans-tri-n-butylstannyl-4-di      methoxymethyl- 2-(7-carbotrimethylsiloxyhexyl)- dl-11α,16-dihydroxy      -9-oxo-16-formyl-  4-trimethylsiloxy-1-octene 4-trimethylsiloxycyclopent-      2-en-1-one 2-homo-13-trans prostenoic acid 11 1-trans-tri-n-butylstannyl-      4-dimethoxymethyl- 2-(7-carbotrimethylsiloxyhexyl)- dl-11α,16-dihyd      roxy-9-oxo-16-formyl-  4-trimethylsiloxy-1-nonene 4-trimethylsiloxycyclop      ent-2-en-1-one 20-methyl-2-homo-13-trans prostenoic acid 12 1-trans-tri-n      -butylstannyl-4-dimethoxymethyl- 2-(7-carbotrimethylsiloxyhexyl)-      dl-11α,16-dihydroxy-9-oxo-16-formyl-  4-trimethylsiloxy-1-decene      4-trimethylsiloxycyclopent-2-en-1-one 20-ethyl-2-homo-13-trans prostenoic       acid 13 1-trans-tri-n-butylstannyl-4-dimethoxymethyl- 2-(6-carbotrimethy      lsiloxy-5-thiahexyl)- dl-11α,16-dihydroxy-9-oxo-16-formyl-      4-trimethylsiloxy-1-heptene 4-trimethylsiloxycyclopent-2-en-1-one      20-nor-3-thia-13-trans prostenoic acid 14 1-trans-tri-n-butylstannyl-4-di      methoxymethyl- 2-(6-carbotrimethylsiloxy-5-thiahexyl)- dl-11α,16-di      hydroxy-9-oxo-16-formyl-  4-trimethylsiloxy-1-octene 4-trimethylsiloxycyc      lopent-2-en-1-one 3-thia-13-trans prostenoic acid 15 1-trans-tri-n-butyls      tannyl-4-dimethoxymethyl- 2-(6-carbotrimethylsiloxy-5-thiahexyl)-      dl-11α,16-dihydroxy-9-oxo-16-formyl-  4-trimethylsiloxy-1-nonene      4-trimethylsiloxycyclopent-2-en-1-one 20-methyl-3-thia-13-trans prostenoi      c acid 16 1-trans-tri-n-butylstannyl-4-dimethoxymethyl- 2-(6-carbotrimeth      ylsiloxy-5-thiahexyl)- dl-11α,16-dihydroxy-9-oxo-16-formyl-      4-trimethylsiloxy-1-decene 4-trimethylsiloxycyclopent-2-en-1-one      20-ethyl-3-thia-13-trans prostenoic acid 17 1-trans-tri-n-butylstannyl-4-      dimethoxymethyl- 2-(6-carbotrimethylsiloxy-5-oxahexyl)- dl-11α,16-d      ihydroxy-9-oxo-16-formyl-  4-trimethylsiloxy-1-heptene 4-trimethylsiloxyc      yclopent-2-en-1-one 20-nor-3-oxa-13-trans prostenoic acid 18 1-trans-tri-      n-butylstannyl-4-dimethoxymethyl- 2-(6-carbotrimethylsiloxy-5-oxahexyl)-      dl-11α,16-dihydroxy-9-oxo-16-formyl-  4-trimethylsiloxy-1-octene      4-trimethylsiloxycyclopent-2-en-1-one 3-oxa-13-trans prostenoic acid 19      1-trans-tri-n-butylstannyl-4-dimethoxymethyl- 2-(6-carbotrimethylsiloxy-5      -oxahexyl)- dl-11α,16-dihydroxy-9-oxo-16-formyl-  4-trimethylsiloxy      -1-nonene 4-trimethylsiloxycyclopent-2-en-1-one 20-methyl-3-oxa-13-trans      prostenoic acid 20 1-trans-tri-n-butylstannyl-4-dimethoxymethyl-      2-(6-carbotrimethylsiloxy-5-oxahexyl)- dl-11α,16-dihydroxy-9-oxo-16      -formyl-  4-trimethylsiloxy-1-decene 4-trimethylsiloxycyclopent-2-en-1-on      e 20-ethyl-3-oxa-13-trans prostenoic acid 21 1-trans-tri-n-butylstannyl-4      -dimethoxymethyl- 2-(6-carbotrimethylsiloxyhexyl)- nat-11α,16-dihyd      roxy-9-oxo-16-formyl-  4-trimethylsiloxy-1-heptene 4R-trimethylsiloxycycl      opent-2-en-1-one 20-nor-13-trans prostenoic acid 22 1-trans-tri-n-butylst      annyl-4-dimethoxymethyl- 2-(6-carbotrimethylsiloxyhexyl)- nat-11α,1      6-dihydroxy-9-oxo-16-formyl-  4-trimethylsiloxy-1-octene 4R-trimethylsilo      xycyclopent-2-en-1-one 13-trans prostenoic acid 23 1-trans-tri-n-butylsta      nnyl-4-dimethoxymethyl- 2-(6-carbotrimethylsiloxyhexyl)- nat-11α,16      -dihydroxy-9-oxo-16-formyl-  4-trimethylsiloxy-1-nonene 4R-trimethylsilox      ycyclopent-2-en-1-one 20-methyl-13-trans prostenoic acid 24 1-trans-tri-n      -butylstannyl-4-dimethoxymethyl- 2-(6-carbotrimethylsiloxyhexyl)-      nat-11α,16-dihydroxy-9-oxo-16-formyl-  4-trimethylsiloxy-1-decene      4R-trimethylsiloxycyclopent-2-en-1-one 20-ethyl-13-trans prostenoic      acid   EXAMPLE VINYL TIN CYCLOPENTENONE PRODUCT PROSTAGLANDIN OF THE      11-DEOXY PGE1 SERIES        25 1-trans-tri-n-butylstannyl-4-dimethoxymethyl- 2-(5-carboethoxypentyl      ) dl-16-hydroxy-9-oxo-16-formyl-  4-trimethylsiloxy-1-heptene cyclopent-2      -en-1-one 20-nor-2-nor-13-trans prostenoic acid 26 1-trans-tri-n-butylsta      nnyl-4-dimethoxymethyl- 2-(5-carboethoxypentyl) dl-16-hydroxy-9-oxo-16-fo      rmyl-  4-trimethylsiloxy-1-octene cyclopent-2-en-1-one 2-nor-13-trans      prostenoic acid 27 1-trans-tri-n-butylstannyl-4-dimethoxymethyl-      2-(5-carboethoxypentyl) dl-16-hydroxy-9-oxo-16-formyl-  4-trimethylsiloxy      -1-nonene cyclopent-2-en-1-one 20-methyl-2-nor-13-trans prostenoic acid      28 1-trans-tri-n-butylstannyl-4-dimethoxymethyl- 2-(5-carboethoxypentyl)      dl-16-hydroxy-9-oxo-16-formyl-  4-trimethylsiloxy-1-decene cyclopent-2-en      -1-one 20-ethyl-2-nor-13-trans prostenoic acid 29 1-trans-tri-n-butylstan      nyl-4-dimethoxymethyl- 2-(6-carboethoxyhexyl) dl-16-hydroxy-9-oxo-16-form      yl-  4-trimethylsiloxy-1-heptene cyclopent-2-en-1-one 20-nor-13-trans      prostenoic acid 30 1-trans-tri-n-butylstannyl-4-dimethoxymethyl-      2-(6-carboethoxyhexyl) dl-16-hydroxy-9-oxo-16-formyl-  4-trimethylsiloxy-      1-octene cyclopent-2-en-1-one 13-trans prostenoic acid 31 1-trans-tri-n-b      utylstannyl-4-dimethoxymethyl- 2-(6-carboethoxyhexyl) dl-16-hydroxy-9-oxo      -16-formyl-  4-trimethylsiloxy-1-nonene cyclopent-2-en-1-one 20-methyl-13      -trans prostenoic acid 32 1-trans-tri-n-butylstannyl-4-dimethoxymethyl-      2-(6-carboethoxyhexyl) dl-16-hydroxy-9-oxo-16-formyl-  4-trimethylsiloxy-      1-decene cyclopent-2-en-1-one 20-ethyl-13-trans prostenoic acid 33      1-trans-tri-n-butylstannyl-4-dimethoxymethyl- 2-(7-carboethoxyheptyl)      dl-16-hydroxy-9-oxo-16-formyl-  4-trimethylsiloxy-1-heptene cyclopent-2-e      n-1-one 20-nor-2-homo-13-trans prostenoic acid 34 1-trans-tri-n-butylstan      nyl-4-dimethoxymethyl- 2-(7-carboethoxyheptyl) dl-16-hydroxy-9-oxo-16-for      myl-  4-trimethylsiloxy-1-octene cyclopent-2-en-1-one 2-homo-13-trans      prostenoic acid 35 1-trans-tri-n-butylstannyl-4-dimethoxymethyl-      2-(7-carboethoxyheptyl) dl-16-hydroxy-9-oxo-16-formyl-  4-trimethylsiloxy      -1-nonene cyclopent-2-en-1-one 20-methyl-2-homo-13-trans prostenoic acid      36 1-trans-tri-n-butylstannyl-4-dimethoxymethyl- 2-(7-carboethoxyheptyl)      dl-16-hydroxy-9-oxo-16-formyl-  4-trimethylsiloxy-1-decene cyclopent-2-en      -1-one 20-ethyl-2-homo-13-trans prostenoic acid 37 1-trans-tri-n-butylsta      nnyl-4-dimethoxymethyl- 2-(6-carboethoxy-5-thiahexyl) dl-16-hydroxy-9-oxo      -16-formyl-  4-trimethylsiloxy-1-heptene cyclopent-2-en-1-one 20-nor-3-th      ia-13-trans prostenoic acid 38 1-trans-tri-n-butylstannyl-4-dimethoxymeth      yl- 2-(6-carboethoxy-5-thiahexyl) dl-16-hydroxy-9-oxo-16-formyl-      4-trimethylsiloxy-1-octene cyclopent-2-en-1-one 3-thia-13-trans prostenoi      c acid 39 1-trans-tri-n-butylstannyl-4-dimethoxymethyl- 2-(6-carboethoxy-      5-thiahexyl) dl-16-hydroxy-9-oxo-16-formyl-  4-trimethylsiloxy-1-nonene      cyclopent-2-en-1-one 20-methyl-3-thia-13-trans prostenoic acid 40      1-trans-tri-n-butylstannyl-4-dimethoxymethyl- 2-(6-carboethoxy-5-thiahexy      l) dl-16-hydroxy-9-oxo-16-formyl-  4-trimethylsiloxy-1-decene cyclopent-2      -en-1-one 20-ethyl-3-thia-13-trans prostenoic acid 41 1-trans-tri-n-butyl      stannyl-4-dimethoxymethyl- 2-(6-carboethoxy-5-oxahexyl) dl-16-hydroxy-9-o      xo-16-formyl-  4-trimethylsiloxy-1-heptene cyclopent-2-en-1-one 20-nor-3-      oxa-13-trans prostenoic acid 42 1-trans-tri-n-butylstannyl-4-dimethoxymet      hyl- 2-(6-carboethoxy-5-oxahexyl) dl-16-hydroxy-9-oxo-16-formyl-      4-trimethylsiloxy-1-octene cyclopent-2-en-1-one 3-oxa-13-trans prostenoic       acid 43 1-trans-tri-n-butylstannyl-4-dimethoxymethyl- 2-(6-carboethoxy-5      -oxahexyl) dl-16-hydroxy-9-oxo-16-methoxymethyl-  4-trimethylsiloxy-1-non      ene cyclopent-2-en-1-one 20-methyl-3-oxa-13-trans prostenoic acid 44      1-trans-tri-n-butylstannyl-4-dimethoxymethyl- 2-(6-carboethoxy-5-oxahexyl      ) dl-16-hydroxy-9-oxo-16-methoxymethyl-  4-trimethylsiloxy-1-decene      cyclopent-2-en-1-one 20-ethyl-3-oxa-13-trans prostenoic acid

Treatment of the PGE₁ derivatives of Examples 1 to 44 (Table I) with lithium perhydro-9b-boraphenalyl hydride by the procedure of Reference Example 6 provides the 16-hydroxy-16-dimethoxymethyl and 16-hydroxy-16-formyl PGF₁α derivatives of Examples 45 to 88 of Table I.

    __________________________________________________________________________     Ex.  STARTING PROSTAGLANDIN OF THE PGE SERIES                                                                   PRODUCT PROSTAGLANDIN OF THE PGF1α                                       SERIES                                        __________________________________________________________________________     45   dl-11α,16-dihydroxy-9-oxo-16-methoxymethyl-                                                          dl-9α,11α,16-trihydroxy-16-fo                                      rmyl-                                              20-nor-2-nor-13-trans prostenoic acid                                                                      20-nor-2-nor-13-trans prostenoic acid         46   dl-11α,16-dihydroxy-9-oxo-16-methoxymethyl-                                                          dl-9α,11α,16-trihydroxy-16-fo                                      rmyl-                                              2-nor-13-trans prostenoic acid                                                                             2-nor-13-trans prostenoic acid                47   dl-11α,16-dihydroxy-9-oxo-16-methoxymethyl-                                                          dl-9α,11α,16-trihydroxy-16-fo                                      rmyl-                                              20-methyl-2-nor-13-trans prostenoic acid                                                                   20-methyl-2-nor-13-trans prostenoic                                            acid                                          48   dl-11α,16-dihydroxy-9-oxo-16-methoxymethyl-                                                          dl-9α,11α,16-trihydroxy-16-fo                                      rmyl-                                              20-ethyl-2-nor-13-trans prostenoic acid                                                                    20-ethyl-2-nor-13-trans prostenoic acid       49   dl-11α,16-dihydroxy-9-oxo-16-methoxymethyl-                                                          dl-9α,11α,16-trihydroxy-16-fo                                      rmyl-                                              20-nor-13-trans prostenoic acid                                                                            20-nor-13-trans prostenoic acid               50   dl-11α,16-dihydroxy-9-oxo-16-methoxymethyl-                                                          dl-9α,11α,16-trihydroxy-16-fo                                      rmyl-                                              13-trans prostenoic acid    13-trans prostenoic acid                      51   dl-11α,16-dihydroxy-9-oxo-16-methoxymethyl-                                                          dl-9α,11α,16-trihydroxy-16-fo                                      rmyl-                                              20-methyl-13-trans prostenoic acid                                                                         20-methyl-13-trans prostenoic acid            52   dl-11α,16-dihydroxy-9-oxo-16-methoxymethyl-                                                          dl-9α,11α,16-trihydroxy-16-fo                                      rmyl-                                              20-ethyl-13-trans prostenoic acid                                                                          20-ethyl-13-trans prostenoic acid             53   dl-11α,16-dihydroxy-9-oxo-16-methoxymethyl-                                                          dl-9α,11α,16-trihydroxy-16-fo                                      rmyl-                                              20-nor-2-homo-13-trans prostenoic acid                                                                     20-nor-2-homo-13-trans prostenoic acid        54   dl-11α,16-dihydroxy-9-oxo-16-methoxymethyl-                                                          dl-9α,11α,16-trihydroxy-16-fo                                      rmyl-                                              2-homo-13-trans prostenoic acid                                                                            2-homo-13-trans prostenoic acid               55   dl-11α,16-dihydroxy-9-oxo-16-methoxymethyl-                                                          dl-9α,11α,16-trihydroxy-16-fo                                      rmyl-                                              20-methyl-2-homo-13-trans prostenoic acid                                                                  20-methyl-2-homo-13-trans prostenoic                                           acid                                          56   dl-11α,16-dihydroxy-9-oxo-16-methoxymethyl-                                                          dl-9α,11α,16-trihydroxy-16-fo                                      rmyl-                                              20-ethyl-2-homo-13-trans prostenoic acid                                                                   2-ethyl-2-homo-13-trans prostenoic acid       57   dl-11α,16-dihydroxy-9-oxo-16-methoxymethyl-                                                          dl-9α,11α,16-trihydroxy-16-fo                                      rmyl-                                              20-nor-3-thia-13-trans prostenoic acid                                                                     20-nor-3-thia-13-trans prostenoic acid        58   dl-11α,16-dihydroxy-9-oxo-16-methoxymethyl-                                                          dl-9α,11α,16-trihydroxy-16-fo                                      rmyl-                                              3-thia-13-trans prostenoic acid                                                                            3-thia-13-trans prostenoic acid               59   dl-11α,16-dihydroxy-9-oxo-16-methoxymethyl-                                                          dl-9α,11α,16-trihydroxy-16-fo                                      rmyl-                                              20-methyl-3-thia-13-trans prostenoic acid                                                                  20-methyl-3-thia-13-trans prostenoic                                           acid                                          60   dl-11α,16-dihydroxy-9-oxo-16-methoxymethyl-                                                          dl-9α,11α,16-trihydroxy-16-fo                                      rmyl-                                              20-ethyl-3-thia-13-trans prostenoic acid                                                                   20-ethyl-3-thia-13-trans prostenoic                                            acid                                          61   dl-11α,16-dihydroxy-9-oxo-16-methoxymethyl-                                                          dl-9α,11α,16-trihydroxy-16-fo                                      rmyl-                                              20-nor-3-oxa-13-trans prostenoic acid                                                                      20-nor-3-oxa-13-trans prostenoic acid         62   dl-11α,16-dihydroxy-9-oxo-16-methoxymethyl-                                                          dl-9α,11α,16-trihydroxy-16-fo                                      rmyl-                                              3-oxa-13-trans prostenoic acid                                                                             3-oxa-13-trans prostenoic acid                63   dl-11α,16-dihydroxy-9-oxo-16-methoxymethyl-                                                          dl-9α,11α,16-trihydroxy-16-fo                                      rmyl-                                              20-methyl-3-oxa-13-trans prostenoic acid                                                                   20-methyl-3-oxa-13-trans prostenoic                                            acid                                          64   dl-11α,16-dihydroxy-9-oxo-16-methoxymethyl-                                                          dl-9α,11α,16-trihydroxy-16-fo                                      rmyl-                                              20-ethyl-3-oxa-13-trans prostenoic acid                                                                    20-ethyl-3-oxa-13-trans prostenoic acid       65   nat-11α,16-dihydroxy-9-oxo-16-methoxymethyl-                                                         nat-9α,11α,16-trihydroxy-16-f                                      ormyl-                                             20-nor-13-trans prostenoic acid                                                                            20-nor-13-trans prostenoic acid               66   nat-11α,16-dihydroxy-9-oxo-16-methoxymethyl-                                                         nat-9α,11α,16-trihydroxy-16-f                                      ormyl-                                             13-trans prostenoic acid    13-trans prostenoic acid                      67   nat-11α,16-dihydroxy-9-oxo-16-methoxymethyl-                                                         nat-9α,11α,16-trihydroxy-16-f                                      ormyl-                                             20-methyl-13-trans prostenoic acid                                                                         20-methyl-13-trans prostenoic acid            68   nat-11α,16-dihydroxy-9-oxo-16-methoxymethyl-                                                         nat-9α,11α,16-trihydroxy-16-f                                      ormyl-                                             20-ethyl-13-trans prostenoic acid                                                                          20-ethyl-13-trans prostenoic                  __________________________________________________________________________                                      acid                                                                           PRODUCT PROSTAGLANDIN OF                      Ex.  STARTING PROSTAGLANDIN OF THE PGE SERIES                                                                   THE 11-DEOXY PGF1α SERIES               __________________________________________________________________________     69   dl-16-hydroxy-9-oxo-16-methoxymethyl-                                                                      dl-9α,16-dihydroxy-16-formyl-                20-nor-2-nor-13-trans prostenoic acid                                                                      20-nor-2-nor-13-trans prostenoic acid         70   dl-16-hydroxy-9-oxo-16-methoxymethyl-                                                                      dl-9α,16-dihydroxy-16-formyl-                2-nor-13-trans prostenoic acid                                                                             2-nor-13-trans prostenoic acid                71   dl-16-hydroxy-9-oxo-16-methoxymethyl-                                                                      dl-9α,16-dihydroxy-16-formyl-                20-methyl-2-nor-13-trans prostenoic acid                                                                   20-methyl-2-nor-13-trans prostenoic                                            acid                                          72   dl-16-hydroxy-9-oxo-16-methoxymethyl-                                                                      dl-9α,16-dihydroxy-16-formyl-                20-ethyl-2-nor-13-trans prostenoic acid                                                                    20-ethyl-2-nor-13-trans prostenoic acid       73   dl-16-hydroxy-9-oxo-16-methoxymethyl-                                                                      dl-9α,16-dihydroxy-16-formyl-                20-nor-13-trans prostenoic acid                                                                            20-nor-13-trans prostenoic acid               74   dl-16-hydroxy-9-oxo-16-methoxymethyl-                                                                      dl-9α,16-dihydroxy-16-formyl-                13-trans prostenoic acid    13-trans prostenoic acid                      75   dl-16-hydroxy-9-oxo-16-methoxymethyl-                                                                      dl-9α,16-dihydroxy-16-formyl-                20-methyl-13-trans prostenoic acid                                                                         20-methyl-13-trans prostenoic acid            76   dl-16-hydroxy-9-oxo-16-methoxymethyl-                                                                      dl-9α,16-dihydroxy-16-formyl-                20-ethyl-13-trans prostenoic acid                                                                          20-ethyl-13-trans prostenoic acid             77   dl-16-hydroxy-9-oxo-16-methoxymethyl-                                                                      dl-9α,16-dihydroxy-16-formyl-                20-nor-2-homo-13-trans prostenoic acid                                                                     20-nor-2-homo-13-trans prostenoic acid        78   dl-16-hydroxy-9-oxo-16-methoxymethyl-                                                                      dl-9α,16-dihydroxy-16-formyl-                2-homo-13-trans prostenoic acid                                                                            2-homo-13-trans prostenoic acid               79   dl-16-hydroxy-9-oxo-16-methoxymethyl-                                                                      dl-9α,16-dihydroxy-16-formyl-                20-methyl-2-homo-13-trans prostenoic acid                                                                  20-methyl-2-homo-13-trans prostenoic                                           acid                                          80   dl-16-hydroxy-9-oxo-16-methoxymethyl-                                                                      dl-9α,16-dihydroxy-16-formyl-                20-ethyl-2-homo-13-trans prostenoic acid                                                                   20-ethyl-2-homo-13-trans prostenoic                                            acid                                          81   dl-16-hydroxy-9-oxo-16-methoxymethyl-                                                                      dl-9α,16-dihydroxy-16-formyl-                20-nor-3-thia-13-trans prostenoic acid                                                                     20-nor-3-thia-13-trans prostenoic acid        82   dl-16-hydroxy-9-oxo-16-methoxymethyl-                                                                      dl-9α,16-dihydroxy-16-formyl-                3-thia-13-trans prostenoic acid                                                                            3-thia-13-trans prostenoic acid               83   dl-16-hydroxy-9-oxo-16-methoxymethyl-                                                                      dl-9α,16-dihydroxy-16-formyl-                20-methyl-3-thia-13-trans prostenoic acid                                                                  20-methyl-3-thia-13-trans prostenoic                                           acid                                          84   dl-16-hydroxy-9-oxo-16-methoxymethyl-                                                                      dl-9α,16-dihydroxy-16-formyl-                20-ethyl-3-thia-13-trans prostenoic acid                                                                   20-ethyl-3-thia-13-trans prostenoic                                            acid                                          85   dl-16-hydroxy-9-oxo-16-methoxymethyl-                                                                      dl-9α,16-dihydroxy-16-formyl-                20-nor-3-oxa-13-trans prostenoic acid                                                                      20-nor-3-oxa-13-trans prostenoic acid         86   dl-16-hydroxy-9-oxo-16-methoxymethyl-                                                                      dl-9α,16-dihydroxy-16-formyl-                3-oxa-13-trans prostenoic acid                                                                             3-oxa-13-trans prostenoic acid                87   dl-16-hydroxy-9-oxo-16-methoxymethyl-                                                                      dl-9α,16-dihydroxy-16-formyl-                20-methyl-3-oxa-13-trans prostenoic acid                                                                   20-methyl-3-oxa-13-trans prostenoic                                            acid                                          88   dl-16-hydroxy-9-oxo-16-methoxymethyl-                                                                      dl-9α,16-dihydroxy-16-formyl-                20-ethyl-3-oxa-13-trans prostenoic acid                                                                    20-ethyl-3-oxa-13-trans prostenoic            __________________________________________________________________________                                      acid                                     

Treatment of the PGE₁ derivatives of Examples 1 to 44 (Table I) with sodium borohydride by the procedure of Reference Example 7 provides the 16-hydroxy-16-formyl PGF₁β derivatives of Examples 89 to 132 (Table I).

    __________________________________________________________________________     EX.  STARTING PROSTAGLANDIN OF THE PGE SERIES                                                                   PRODUCT PROSTAGLANDIN OF THE PGF1β                                        SERIES                                        __________________________________________________________________________      89  dl-11α,16-dihydroxy-9-oxo-16-methoxymethyl-                                                          dl-9β,11α,16-trihydroxy-16-for                                      myl-                                               20-nor-2-nor-13-trans prostenoic acid                                                                      20-nor-2-nor-13-trans prostenoic acid          90  dl-11α,16-dihydroxy-9-oxo-16-methoxymethyl-                                                          dl-9β,11α,16-trihydroxy-16-for                                      myl-                                               2-nor-13-trans prostenoic acid                                                                             2-nor-13-trans prostenoic acid                 91  dl-11α,16-dihydroxy-9-oxo-16-methoxymethyl-                                                          dl-9β,11α,16-trihydroxy-16-for                                      myl-                                               20-methyl-2-nor-13-trans prostenoic acid                                                                   20-methyl-2-nor-13-trans prostenoic                                            acid                                           92  dl-11α,16-dihydroxy-9-oxo-16-methoxymethyl-                                                          dl-9β,11α,16-trihydroxy-16-for                                      myl-                                               20-ethyl-2-nor-13-trans prostenoic acid                                                                    20-ethyl-2-nor-13-trans prostenoic acid        93  dl-11α,16-dihydroxy-9-oxo-16-methoxymethyl-                                                          dl-9β,11α,16-trihydroxy-16-for                                      myl-                                               20-nor-13-trans prostenoic acid                                                                            20-nor-13-trans prostenoic acid                94  dl-11α,16-dihydroxy-9-oxo-16-methoxymethyl-                                                          dl-9β,11α,16-trihydroxy-16-for                                      myl-                                               13-trans prostenoic acid    13-trans prostenoic acid                       95  dl-11α,16-dihydroxy-9-oxo-16-methoxymethyl-                                                          dl-9β,11α,16-trihydroxy-16-for                                      myl-                                               20-methyl-13-trans prostenoic acid                                                                         20-methyl-13-trans prostenoic acid             96  dl-11α,16-dihydroxy-9-oxo-16-methoxymethyl-                                                          dl-9β,11α,16-trihydroxy-16-for                                      myl-                                               20-ethyl-13-trans prostenoic acid                                                                          20-ethyl-13-trans prostenoic acid              97  dl-11α,16-dihydroxy-9-oxo-16-methoxymethyl-                                                          dl-9β,11α,16-trihydroxy-16-for                                      myl-                                               20-nor-2-homo-13-trans prostenoic acid                                                                     20-nor-2-homo-13-trans prostenoic acid         98  dl-11α,16-dihydroxy-9-oxo-16-methoxymethyl-                                                          dl-9β,11α,16-trihydroxy-16-for                                      myl-                                               2-homo-13-trans prostenoic acid                                                                            2-homo-13-trans prostenoic acid                99  dl-11α,16-dihydroxy-9-oxo-16-methoxymethyl-                                                          dl-9β,11α,16-trihydroxy-16-for                                      myl-                                               20-methyl-2-homo-13-trans prostenoic acid                                                                  20-methyl-2-homo-13-trans prostenoic                                           acid                                          100  dl-11α,16-dihydroxy-9-oxo-16-methoxymethyl-                                                          dl-9β,11α,16-trihydroxy-16-for                                      myl-                                               20-ethyl-2-homo-13-trans prostenoic acid                                                                   20-ethyl-2-homo-13-trans prostenoic                                            acid                                          101  dl-11α,16-dihydroxy-9-oxo-16-methoxymethyl-                                                          dl-9β,11α,16-trihydroxy-16-for                                      myl-                                               20-nor-3-thia-13-trans prostenoic acid                                                                     20-nor-3-thia-13-trans prostenoic acid        102  dl-11α,16-dihydroxy-9-oxo-16-methoxymethyl-                                                          dl-9β,11α,16-trihydroxy-16-for                                      myl-                                               3-thia-13-trans prostenoic acid                                                                            3-thia-13-trans prostenoic acid               103  dl-11α,16-dihydroxy-9-oxo-16-methoxymethyl-                                                          dl-9β,11α,16-trihydroxy-16-for                                      myl-                                               20-methyl-3-thia-13-trans prostenoic acid                                                                  20-methyl-3-thia-13-trans prostenoic                                           acid                                          104  dl-11α,16-dihydroxy-9-oxo-16-methoxymethyl-                                                          dl-9β,11α,16-trihydroxy-16-for                                      myl-                                               20-ethyl-3-thia-13-trans prostenoic acid                                                                   20-ethyl-3-thia-13-trans prostenoic                                            acid                                          105  dl-11α,16-dihydroxy-9-oxo-16-methoxymethyl-                                                          dl-9β,11α,16-trihydroxy-16-for                                      myl-                                               20-nor-3-oxa-13-trans prostenoic acid                                                                      20-nor-3-oxa-13-trans prostenoic acid         106  dl-11α,16-dihydroxy-9-oxo-16-methoxymethyl-                                                          dl-9β,11α,16-trihydroxy-16-for                                      myl-                                               3-oxa-13-trans prostenoic acid                                                                             3-oxa-13-trans prostenoic acid                107  dl-11α,16-dihydroxy-9-oxo-16-methoxymethyl-                                                          dl-9β,11α,16-trihydroxy-16-for                                      myl-                                               20-methyl-3-oxa-13-trans prostenoic acid                                                                   20-methyl-3-oxa-13-trans prostenoic                                            acid                                          108  dl-11α,16-dihydroxy-9-oxo-16-methoxymethyl-                                                          dl-9β,11α,16-trihydroxy-16-for                                      myl-                                               20-ethyl-3-oxa-13-trans prostenoic acid                                                                    20-ethyl-3-oxa-13-trans prostenoic acid       109  nat-11α,16-dihydroxy-9-oxo-16-methoxymethyl-                                                         nat-9β,11α,16-trihydroxy-16-fo                                      rmyl-                                              20-nor-13-trans prostenoic acid                                                                            20-nor-13-trans prostenoic acid               110  nat-11α,16-dihydroxy-9-oxo-16-methoxymethyl-                                                         nat-9β,11α,16-trihydroxy-16-fo                                      rmyl-                                              13-trans prostenoic acid    13-trans prostenoic acid                      111  nat-11α,16-dihydroxy-9-oxo-16-methoxymethyl-                                                         nat-9β ,11α,16-trihydroxy-16-f                                      ormyl-                                             20-methyl-13-trans prostenoic acid                                                                         20-methyl-13-trans prostenoic acid            112  nat-11α,16-dihydroxy-9-oxo-16-methoxymethyl-                                                         nat-9β,11α,16-trihydroxy-16-fo                                      rmyl-                                              20-ethyl-13-trans prostenoic acid                                                                          20-ethyl-13-trans prostenoic                  __________________________________________________________________________                                      acid                                                                           PRODUCT PROSTAGLANDIN OF                      EX.  STARTING PROSTAGLANDIN OF THE PGE SERIES                                                                   THE 11-DEOXY PGF1β                       __________________________________________________________________________                                      SERIES                                        113  dl-16-hydroxy-9-oxo-16-methoxymethyl-                                                                      dl-9β,16-dihydroxy-16-formyl-                 20-nor-2-nor-13-trans prostenoic acid                                                                      20-nor-2-nor-13-trans prostenoic acid         114  dl-16-hydroxy-9-oxo-16-methoxymethyl-                                                                      dl-9β,16-dihydroxy-16-formyl-                 2-nor-13-trans prostenoic acid                                                                             2-nor-13-trans prostenoic acid                115  dl-16-hydroxy-9-oxo-16-methoxymethyl-                                                                      dl-9β,16-dihydroxy-16-formyl-                 20-methyl-2-nor-13-trans prostenoic acid                                                                   20-methyl-2-nor-13-trans prostenoic                                            acid                                          116  dl-16-hydroxy-9-oxo-16-methoxymethyl-                                                                      dl-9β,16-dihydroxy-16-formyl-                 20-ethyl-2-nor-13-trans prostenoic acid                                                                    20-ethyl-2-nor-13-trans prostenoic acid       117  dl-16-hydroxy-9-oxo-16-methoxymethyl-                                                                      dl-9β,16-dihydroxy-16-formyl-                 20-nor-13-trans prostenoic acid                                                                            20-nor-13-trans prostenoic acid               118  dl-16-hydroxy-9-oxo-16-methoxymethyl-                                                                      dl-9β,16-dihydroxy-16-formyl-                 13-trans prostenoic acid    13-trans prostenoic acid                      119  dl-16-hydroxy-9-oxo-16-methoxymethyl-                                                                      dl-9β,16-dihydroxy-16-formyl-                 20-methyl-13-trans prostenoic acid                                                                         20-methyl-13-trans prostenoic acid            120  dl-16-hydroxy-9-oxo-16-methoxymethyl-                                                                      dl-9β,16-dihydroxy-16-formyl-                 20-ethyl-13-trans prostenoic acid                                                                          20-ethyl-13-trans prostenoic acid             121  dl-16-hydroxy-9-oxo-16-methoxymethyl-                                                                      dl-9β,16-dihydroxy-16-formyl-                 20-nor-2-homo-13-trans prostenoic acid                                                                     20-nor-2-homo-13-trans prostenoic acid        122  dl-16-hydroxy-9-oxo-16-methoxymethyl-                                                                      dl-9β,16-dihydroxy-16-formyl-                 2-homo-13-trans prostenoic acid                                                                            2-homo-13-trans prostenoic acid               123  dl-16-hydroxy-9-oxo-16-methoxymethyl-                                                                      dl-9β  ,16-dihydroxy-16-formyl-               20-methyl-2-homo-13-trans prostenoic acid                                                                  20-methyl-2-homo-13-trans prostenoic                                           acid                                          124  dl-16-hydroxy-9-oxo-16-methoxymethyl-                                                                      dl-9β,16-dihydroxy-16-formyl-                 20-ethyl-2-homo-13-trans prostenoic acid                                                                   20-ethyl-2-homo-13-trans prostenoic                                            acid                                          125  dl-16-hydroxy-9-oxo-16-methoxymethyl-                                                                      dl-9β,16-dihydroxy-16-formyl-                 20-nor-3-thia-13-trans prostenoic acid                                                                     20-nor-3-thia-13-trans prostenoic acid        126  dl-16-hydroxy-9-oxo-16-methoxymethyl-                                                                      dl-9β,16-dihydroxy-16-formyl-                 3-thia-13-trans prostenoic acid                                                                            3-thia-13-trans prostenoic acid               127  dl-16-hydroxy-9-oxo-16-methoxymethyl-                                                                      dl-9β,16-dihydroxy-16-formyl-                 20-methyl-3-thia-13-trans prostenoic acid                                                                  20-methyl-3-thia-13-trans prostenoic                                           acid                                          128  dl-16-hydroxy-9-oxo-16-methoxymethyl-                                                                      dl-9β,16-dihydroxy-16-formyl-                 20-ethyl-3-thia-13-trans prostenoic acid                                                                   20-ethyl-3-thia-13-trans prostenoic                                            acid                                          129  dl-16-hydroxy-9-oxo-16-methoxymethyl-                                                                      dl-9β,16-dihydroxy-16-formyl-                 20-nor-3-oxa-13-trans prostenoic acid                                                                      20-nor-3-oxa-13-trans prostenoic acid         130  dl-16-hydroxy-9-oxo-16-methoxymethyl-                                                                      dl-9β,16-dihydroxy-16-formyl-                 3-oxa-13-trans prostenoic acid                                                                             3-oxa-13-trans prostenoic acid                131  dl-16-hydroxy-9-oxo-16-methoxymethyl-                                                                      dl-9β,16-dihydroxy-16-formyl-                 20-methyl-3-oxa-13-trans prostenoic acid                                                                   20-methyl-3-oxa-13-trans prostenoic                                            acid                                          132  dl-16-hydroxy-9-oxo-16-methoxymethyl-                                                                      dl-9β,16-dihydroxy-16-formyl-                 20-ethyl-3-oxa-13-trans prostenoic acid                                                                    20-ethyl-3-oxa-13-trans prostenoic            __________________________________________________________________________                                      acid                                     

TABLE II

Treatment of the cyclopentenones of Table B with the lithiocuprates generated from Reference Examples 3 and 10 by the procedure of reference Example 4 provides the 16-hydroxy-16 dimethoxymethyl derivatives that upon mild acid hydrolysis procedure of Reference Example 6 generate the 16-hydroxy-16-formyl PGE₂ derivatives of Examples 1 to 28 of Table II.

      EXAMPLE VINYL TIN CYCLOPENTENONE PRODUCT PROSTAGLANDIN OF THE PGE2      SERIES        1 1-trans-tri-n-butylstannyl-4-dimethoxymethyl- 2-(5-carbotrimethylsilo      xypent-2-cis-enyl)- dl-11α,16-dihydroxy-9-oxo-16-formyl-  4-trimeth      ylsiloxy-1-heptene 4-trimethylsiloxycyclopent-2-en-1-one 20-nor-2-nor-5-c      is-13-trans prostadienoic acid 2 1-trans-tri-n-butylstannyl-4-dimethoxyme      thyl- 2-(5-carbotrimethylsiloxypent-2-cis-enyl)- dl-11α,16-dihydrox      y-9-oxo-16-formyl-  4-trimethylsiloxy-1-octene 4-trimethylsiloxycyclopent      -2-en-1-one 2-nor-5-cis-13-trans prostadienoic acid 3 1-trans-tri-n-butyl      stannyl-4-dimethoxymethyl- 2-(5-carbotrimethylsiloxypent-2-cis-enyl)-      dl-11α,16-dihydroxy-9-oxo-16-formyl-  4-trimethylsiloxy-1-nonene      4-trimethylsiloxycyclopent-2-en-1-one 20-methyl-2-nor-5-cis-13-trans      prostadienoic acid 4 1-trans-tri-n-butylstannyl-4-dimethoxymethyl-      2-(5-carbotrimethylsiloxypent-2-cis-enyl)- dl-11α,16-dihydroxy-9-ox      o-16-formyl-  4-trimethylsiloxy-1-decene 4-trimethylsiloxycyclopent-2-en-      1-one 20-ethyl-2-nor-5-cis-13-trans prostadienoic acid 5 1-trans-tri-n-bu      tylstannyl-4-dimethoxymethyl- 2-(6-carbotrimethylsiloxyhex-2-cis-enyl)-      dl-11α,16-dihydroxy-9-oxo-16-formyl-  4-trimethylsiloxy-1-heptene      4-trimethylsiloxycyclopent-2-en-1-one 20-nor-5-cis-13-trans prostadienoic       acid 6 1-trans-tri-n-butylstannyl-4-dimethoxymethyl- 2-(6-carbotrimethyl      siloxyhex-2-cis-enyl)- dl-11α,16-dihydroxy-9-oxo-16-formyl-      4-trimethylsiloxy-1-octene 4-trimethylsiloxycyclopent-2-en-1-one      5-cis-13-trans prostadienoic acid 7 1-trans-tri-n-butylstannyl-4-dimethox      ymethyl- 2-(6-carbotrimethylsiloxyhex-2-cis-enyl)- dl-11α,16-dihydr      oxy-9-oxo-16-formyl-  4-trimethylsiloxy-1-nonene 4-trimethylsiloxycyclope      nt-2-en-1-one 20-methyl-5-cis-13-trans prostadienoic acid 8 1-trans-tri-n      -butylstannyl-4-dimethoxymethyl- 2-(6-carbotrimethylsiloxyhex-2-cis-enyl)      - dl-11α,16-dihydroxy-9-oxo-16-formyl-  4-trimethylsiloxy-1-decene      4-trimethylsiloxycyclopent-2-en-1-one 20-ethyl-5-cis-13-trans prostadieno      ic acid 9 1-trans-tri-n-butylstannyl-4-dimethoxymethyl- 2-(7-carbotrimeth      ylsiloxyhept-2-cis-enyl)- dl-11α,16-dihydroxy-9-oxo-16-formyl-      4-trimethylsiloxy-1-heptene 4-trimethylsiloxycyclopent-2-en-1-one      20-nor-2-homo-5-cis-13-trans prostadienoic acid 10 1-trans-tri-n-butylsta      nnyl-4-dimethoxymethyl- 2-(7-carbotrimethylsiloxyhept-2-cis-enyl)-      dl-11α,16-dihydroxy-9-oxo-16-formyl-  4-trimethylsiloxy-1-octene      4-trimethylsiloxycyclopent-2-en-1-one 2-homo-5-cis-13-trans prostadienoic       acid 11 1-trans-tri-n-butylstannyl-4-dimethoxymethyl- 2-(7-carbotrimethy      lsiloxyhept-2-cis-enyl)- dl-11α,16-dihydroxy-9-oxo-16-formyl-      4-trimethylsiloxy-1-nonene 4-trimethylsiloxycyclopent-2-en-1-one      20-methyl-2-homo-5-cis-13-trans prostadienoic acid 12 1-trans-tri-n-butyl      stannyl-4-dimethoxymethyl- 2-(7-carbotrimethylsiloxyhept-2-cis-enyl)-      dl-11α,16-dihydroxy-9-oxo-16-formyl-  4-trimethylsiloxy-1-decene      4-trimethylsiloxycyclopent-2-en-1-one 20-ethyl-2-homo-5-cis-13-trans      prostadienoic acid 13 1-trans-tri-n-butylstannyl-4-dimethoxymethyl-      2-(6-carbotrimethylsiloxyhex-2-cis-enyl)- nat-11α,16-dihydroxy-9-ox      o-16-formyl-  4-trimethylsiloxy-1-heptene 4R-trimethylsiloxycyclopent-2-e      n-1-one 20-nor-5-cis-13-trans prostadienoic acid 14 1-trans-tri-n-butylst      annyl-4-dimethoxymethyl- 2-(6-carbotrimethylsiloxyhex-2-cis-enyl)-      nat-11α,16-dihydroxy-9-oxo-16-formyl-  4-trimethylsiloxy-1-octene      4R-trimethylsiloxycyclopent-2-en-1-one 5-cis-13-trans prostadienoic acid      15 1-trans-tri-n-butylstannyl-4-dimethoxymethyl- 2-(6-carbotrimethylsilox      yhex-2-cis-enyl)- nat-11α,16-dihydroxy-9-oxo-16-formyl-  4-trimethy      lsiloxy-1-nonene 4R-trimethylsiloxycyclopent-2-en-1-one 20-methyl-5-cis-1      3-trans prostadienoic acid 16 1-trans-tri-n-butylstannyl-4-dimethoxymethy      l- 2-(6-carbotrimethylsiloxyhex-2-cis-enyl)- nat-11α,16-dihydroxy-9      -oxo-16-formyl-  4-trimethylsiloxy-1-decene 4R-trimethylsiloxycyclopent-2      -en-1-one 20-ethyl-5-cis-13-trans prostadienoic acid        EXAMPLE VINYL TIN CYCLOPENTENONE PRODUCT PROSTAGLANDIN OF THE 11-DEOXY      PGE2 SERIES        17 1-trans-tri-n-butylstannyl-4-dimethoxymethyl- 2-(5-carboethoxypent-2      -cis-enyl)- dl-16-hydroxy-9-oxo-16-formyl-  4-trimethylsiloxy-1-heptene      cyclopent-2-en-1-one 20-nor-2-nor-5-cis-13-trans prosadienoic acid 18      1-trans-tri-n-butylstannyl-4-dimethoxymethyl- 2-(5-carboethoxypent-2-cis-      enyl) dl-16-hydroxy-9-oxo-16-formyl-  4-trimethylsiloxy-1-octene      cyclopent-2-en-1-one 2-nor-5-cis-13-trans prostadienoic acid 19 1-trans-t      ri-n-butylstannyl-4-dimethoxymethyl- 2-(5-carboethoxypent-2-cis-enyl)      dl-16-hydroxy-9-oxo-16-formyl-  4-trimethylsiloxy-1-nonene cyclopent-2-en      -1-one 20-methyl-2-nor-5-cis-13-trans prostadienoic acid 20 1-trans-tri-n      -butylstannyl-4-dimethoxymethyl- 2-(5-carboethoxypent-2-cis-enyl)      dl-16-hydroxy-9-oxo-16-formyl-  4-trimethylsiloxy-1-decene cyclopent-2-en      -1-one 20-ethyl-2-nor-5-cis-13-trans prostadienoic acid 21 1-trans-tri-n-      butylstannyl-4-dimethoxymethyl- 2-(6-carboethoxyhex-2-cis-enyl) dl-16-hyd      roxy-9-oxo-16-formyl-  4-trimethylsiloxy-1-heptene cyclopent-2-en-1-one      20-nor-5-cis-13-trans prostadienoic acid 22 1-trans-tri-n-butylstannyl-4-      dimethoxymethyl- 2-(6-carboethoxyhex-2-cis-enyl) dl-16-hydroxy-9-oxo-16-f      ormyl-  4-trimethylsiloxy-1-octene cyclopent-2-en-1-one 5-cis-13-trans      prostadienoic acid 23 1-trans-tri-n-butylstannyl-4-dimethoxymethyl-      2-(6-carboethoxyhex-2-cis-enyl) dl-16-hydroxy-9-oxo-16-formyl-  4-trimeth      ylsiloxy-1-nonene cyclopent-2-en-1-one 20-methyl-5-cis-13-trans prostadie      noic acid 24 1-trans-tri-n-butylstannyl-4-dimethoxymethyl- 2-(6-carboetho      xyhex-2-cis-enyl) dl-16-hydroxy-9-oxo-16-formyl-  4-trimethylsiloxy-1-dec      ene cyclopent-2-en-1-one 20-ethyl-5-cis-13-trans prostadienoic acid 25      1-trans-tri-n-butylstannyl-4-dimethoxymethyl- 2-(7-carboethoxyhept-2-cis-      enyl) dl-16-hydroxy-9-oxo-16-formyl-  4-trimethylsiloxy-1-heptene      cyclopent-2-en-1-one 20-nor-2-homo-5-cis-13-trans prostadienoic acid 26      1-trans-tri-n-butylstannyl-4-dimethoxymethyl- 2-(7-carboethoxyhept-2-cis-      enyl) dl-16-hydroxy-9-oxo-16-formyl-  4-trimethylsiloxy-1-octene      cyclopent-2-en-1-one 2-homo-5-cis-13-trans prostadienoic acid 27      1-trans-tri-n-butylstannyl-4-dimethoxymethyl- 2-(7-carboethoxyhept-2-cis-      enyl) dl-16-hydroxy-9-oxo-16-formyl-  4-trimethylsiloxy-1-nonene      cyclopent-2-en-1-one 20-methyl-2-homo-5-cis-13-trans prostadienoic acid      28 1-trans-tri-n-butylstannyl-4-dimethoxymethyl- 2-(7-carboethoxyhept-2-c      is-enyl) dl-16-hydroxy-9-oxo-16-dimethoxymethyl-  4-trimethylsiloxy-1-dec      ene cyclopent-2-en-1-one 20-ethyl-2-homo-5-cis-13-trans prostadienoic      acid

Treatment of the PGE₂ derivatives of Examples 1 to 28 (Table II) with lithium perhydro-9b -boraphenalyl hydride by the procedure of Reference Example 6 provides the 16 -hydroxy-16 dimethoxymethyl and 16-hydroxy-16-formyl PGF₂α derivatives of Examples 29 to 56 of Table II.

    __________________________________________________________________________            STARTING PROSTAGLANDIN  PRODUCT PROSTAGLANDIN                           EXAMPLE                                                                               OF THE PGE SERIES       OF THE PGF.sub.2α SERIES                  __________________________________________________________________________     29     dl-11α,16-dihydroxy-9-oxo-16-dimethoxymethyl-                                                    dl-9α,11α,16-trihydroxy-16-form                                    yl-                                                    20-nor-2-nor-5-cis-13-trans prostadienoic acid                                                         20-nor-2-nor-5-cis-13-trans prostadienoic                                      acid                                            30     dl-11α,16-dihydroxy-9-oxo-16-dimethoxymethyl-                                                    dl-9α,11α,16-trihydroxy-16-form                                    yl-                                                    2-nor-5-cis-13-trans prostadienoic acid                                                                2-nor-5-cis-13-trans prostadienoic acid         31     dl-11α,16-dihydroxy-9-oxo-16-dimethoxymethyl-                                                    dl-9α,11α,16-trihydroxy-16-form                                    yl-                                                    20-methyl-2-nor-5-cis-13-trans prostadienoic acid                                                      20-methyl-2-nor-5-cis-13-trans                                                 prostadienoic acid                              32     dl-11α,16-dihydroxy-9-oxo-16-dimethoxymethyl-                                                    dl-9α,11α,16-trihydroxy-16-form                                    yl-                                                    20-ethyl-2-nor-5-cis-13-trans prostadienoic acid                                                       20-ethyl-2-nor-5-cis-13-trans                                                  prostadienoic acid                              33     dl-11α,16-dihydroxy-9-oxo-16-dimethoxymethyl-                                                    dl-9α,11α,16-trihydroxy-16-form                                    yl-                                                    20-nor-5-cis-13-trans prostadienoic acid                                                               20-nor-5-cis-13-trans prostadienoic acid        34     dl-11α,16-dihydroxy-9-oxo-16-dimethoxymethyl-                                                    dl-9α,11α,16-trihydroxy-16-form                                    yl-                                                    5-cis-13-trans prostadienoic acid                                                                      5-cis-13-trans prostadienoic acid               35     dl-11α,16-dihydroxy-9-oxo-16-dimethoxymethyl-                                                    dl-9α,11α,16-trihydroxy-16-form                                    yl-                                                    20-methyl- 5-cis-13-trans prostadienoic acid                                                           20-methyl-5-cis-13-trans prostadienoic                                         acid                                            36     dl-11α,16-dihydroxy-9-oxo-16-dimethoxymethyl-                                                    dl-9α,11α,16-trihydroxy-16-form                                    yl-                                                    20-ethyl-5-cis-13-trans prostadienoic acid                                                             20-ethyl-5-cis-13-trans prostadienoic                                          acid                                            37     dl-11α,16-dihydroxy-9-oxo-16-dimethoxymethyl-                                                    dl-9α,11α,16-trihydroxy-16-form                                    yl-                                                    20-nor-2-homo-5-cis-13-trans prostadienoic acid                                                        20-nor-2-homo-5-cis-13-trans prostadienoic                                     acid                                            38     dl-11α,16-dihydroxy-9-oxo-16-dimethoxymethyl-                                                    dl-9α,11α,16-trihydroxy-16-form                                    yl-                                                    2-homo-5-cis-13-trans prostadienoic acid                                                               2-homo-5-cis-13-trans prostadienoic acid        39     dl-11α,16-dihydroxy-9-oxo-16-dimethoxymethyl-                                                    dl-9α,11α,16-trihydroxy-16-form                                    yl-                                                    20-methyl-2-homo-5-cis-13-trans prostadienoic acid                                                     20-methyl-2-homo-5-cis-13-trans                                                prostadienoic acid                              40     dl-11α,16-dihydroxy-9-oxo-16-dimethoxymethyl-                                                    dl-9α,11α,16-trihydroxy-16-form                                    yl-                                                    20-ethyl-2-homo-5-cis-13-trans prostadienoic acid                                                      20-ethyl-2-homo-5-cis-13-trans                                                 prostadienoic acid                              41     nat-11α,16-dihydroxy-9-oxo-16-dimethoxymethyl-                                                   nat-9α,11α,16-trihydroxy-16-for                                    myl-                                                   20-nor-5-cis-13-trans prostadienoic acid                                                               20-nor-5-cis-13-trans prostadienoic acid        42     nat-11α,16-dihydroxy-9-oxo-16-dimethoxymethyl-                                                   nat-9α,11α,16-trihydroxy-16-for                                    myl-                                                   5-cis-13-trans prostadienoic acid                                                                      5-cis-13-trans prostadienoic acid               43     nat-11α,16-dihydroxy-9-oxo-16-dimethoxymethyl-                                                   nat-9α,11α,16-trihydroxy-16-for                                    myl-                                                   20-methyl-5-cis-13-trans prostadienoic acid                                                            20-methyl-5-cis-13-trans prostadienoic                                         acid                                            44     nat-11α,16-dihydroxy-9-oxo-16-dimethoxymethyl-                                                   nat-9α,11α,16-trihydroxy-16-for                                    myl-                                                   20-ethyl-5-cis-13-trans prostadienoic acid                                                             20-ethyl-5-cis-13-trans prostadienoic           __________________________________________________________________________                                    acid                                                   STARTING PROSTAGLANDIN  PRODUCT PROSTAGLANDIN OF                        EXAMPLE                                                                               OF THE PGE SERIES       THE 11-DEOXY PGF.sub.2α  SERIES           __________________________________________________________________________     45     dl-16-hydroxy-9-oxo-16-dimethoxymethyl-                                                                dl-9α,16-dihydroxy-16-formyl-                    20-nor-2-nor-5-cis-13-trans prostadienoic acid                                                         20-nor-2-nor-5-cis-13-trans prostadienoic                                      acid                                            46     dl-16-hydroxy-9-oxo-16-dimethoxymethyl-                                                                dl-9α,16-dihydroxy-16-formyl-                    2-nor-5-cis-13-trans prostadienoic acid                                                                2-nor-5-cis-13-trans prostadienoic acid         47     dl-16-hydroxy-9-oxo-16-dimethoxymethyl-                                                                dl-9α,16-dihydroxy-16-formyl-                    20-methyl-2-nor-5-cis-13-trans prostadienoic acid                                                      20-methyl-2-nor-5-cis-13-trans                                                 prostadienoic acid                              48     dl-16-hydroxy-9-oxo-16-dimethoxymethyl-                                                                dl-9α,16-dihydroxy-16-formyl-                    20-ethyl-2-nor-5-cis-13-trans prostadienoic acid                                                       20-ethyl-2-nor-5-cis-13-trans                                                  prostadienoic acid                              49     dl-16-hydroxy-9-oxo-16-dimethoxymethyl-                                                                dl-9α,16-dihydroxy-16-formyl-                    20-nor-5-cis-13-trans prostadienoic acid                                                               20-nor-5-cis-13-trans prostadienoic acid        50     dl-16-hydroxy-9-oxo-16-dimethoxymethyl-                                                                dl-9α,16-dihydroxy-16-formyl-                    5-cis-13-trans prostadienoic acid                                                                      5-cis-13-trans prostadienoic acid               51     dl-16-hydroxy-9-oxo-16-dimethoxymethyl-                                                                dl-9α,16-dihydroxy-16-formyl-                    20-methyl-5-cis-13-trans prostadienoic acid                                                            20-methyl-5-cis-13-trans prostadienoic                                         acid                                            52     dl-16-hydroxy-9-oxo-16-dimethoxymethyl-                                                                dl-9α,16-dihydroxy-16-formyl-                    20-ethyl-5-cis-13-trans prostadienoic acid                                                             20-ethyl-5-cis-13-trans prostadienoic                                          acid                                            53     dl-16-hydroxy-9-oxo-16-dimethoxymethyl-                                                                dl-9α,16-dihydroxy-16-formyl-                    20-nor-2-homo-5-cis-13-trans prostadienoic acid                                                        20-nor-2-homo-5-cis-13-trans prostadienoic                                     acid                                            54     dl-16-hydroxy-9-oxo-16-dimethoxymethyl-                                                                dl-9α,16-dihydroxy-16-formyl-                    2-homo-5-cis-13-trans prostadienoic acid                                                               2-homo-5-cis-13-trans prostadienoic acid        55     dl-16-hydroxy-9-oxo-16-dimethoxymethyl-                                                                dl-9α,16-dihydroxy-16-formyl-                    20-methyl-2-homo-5-cis-13-trans prostadienoic acid                                                     20-methyl-2-homo-5-cis-13-trans                                                prostadienoic acid                              56     dl-16-hydroxy-9-oxo-16-dimethoxymethyl-                                                                dl-9α,16-dihydroxy-16-formyl-                    20-ethyl-2-homo-5-cis-13-trans prostadienoic acid                                                      20-ethyl-2-homo-5-cis-13-trans                                                 prostadienoic acid                              __________________________________________________________________________

Treatment of the PGE₂ derivative of Examples 1 to 28 (Table II) with sodium borohydride by the procedure of Reference Example 7 provides the 16-hydroxy-16-dimethoxymethyl and 16-hydroxy-16-formyl PGF₂β derivatives of Examples 57 to 84 of Table II.

    __________________________________________________________________________            STARTING PROSTAGLANDIN  PRODUCT PROSTAGLANDIN                           EXAMPLE                                                                               OF THE PGE SERIES       OF THE PGF.sub.2β  SERIES                  __________________________________________________________________________     57     dl-11α,16-dihydroxy-9-oxo-16-dimethoxymethyl-                                                    dl-9β,11α,16-trihydroxy-16-formy                                    l-                                                     20-nor-2-nor-5-cis-13-trans prostadienoic acid                                                         20-nor-2-nor-5-cis-13-trans prostadienoic                                      acid                                            58     dl-11α,16-dihydroxy-9-oxo-16-dimethoxymethyl-                                                    dl-9β,11α,16-trihydroxy-16-formy                                    l-                                                     2-nor-5-cis-13-trans prostadienoic acid                                                                2-nor-5-cis-13-trans prostadienoic acid         59     dl-11α,16-dihydroxy-9-oxo-16-dimethoxymethyl-                                                    dl-9β,11α,16-trihydroxy-16-formy                                    l-                                                     20-methyl-2-nor-5-cis-13-trans prostadienoic acid                                                      20-methyl-2-nor-5-cis-13-trans                                                 prostadienoic acid                              60     dl-11α,16-dihydroxy-9-oxo-16-dimethoxymethyl-                                                    dl-9β,11α,16-trihydroxy-16-formy                                    l-                                                     20-ethyl-2-nor-5-cis-13-trans prostadienoic acid                                                       20-ethyl-2-nor-5-cis-13-trans                                                  prostadienoic acid                              61     dl-11α,16-dihydroxy-9-oxo-16-dimethoxymethyl-                                                    dl-9β,11α,16-trihydroxy-16-formy                                    l-                                                     20-nor-5-cis-13-trans prostadienoic acid                                                               20-nor-5-cis-13-trans prostadienoic acid        62     dl-11α,16-dihydroxy-9-oxo-16-dimethoxymethyl-                                                    dl-9β,11α,16-trihydroxy-16-formy                                    l-                                                     5-cis-13-trans prostadienoic acid                                                                      5-cis-13-trans prostadienoic acid               63     dl-11α,16-dihydroxy-9-oxo-16-dimethoxymethyl-                                                    dl-9β,11α,16-trihydroxy-16-formy                                    l-                                                     20-methyl-5-cis-13-trans prostadienoic acid                                                            20-methyl-5-cis-13-trans prostadienoic                                         acid                                            64     dl-11α,16-dihydroxy-9-oxo-16-dimethoxymethyl-                                                    dl-9β,11α,16-trihydroxy-16-formy                                    l-                                                     20-ethyl-5-cis-13-trans prostadienoic acid                                                             20-ethyl-5-cis-13-trans prostadienoic                                          acid                                            65     dl-11α,16-dihydroxy-9-oxo-16-dimethoxymethyl-                                                    dl-9β,11α,16-trihydroxy-16-formy                                    l-                                                     20-nor-2-homo-5-cis-13-trans prostadienoic acid                                                        20-nor-2-homo-5-cis-13-trans prostadienoic                                     acid                                            66     dl-11α,16-dihydroxy-9-oxo-16-dimethoxymethyl-                                                    dl-9β,11α,16-trihydroxy-16-formy                                    l-                                                     2-homo-5-cis-13-trans prostadienoic acid                                                               2-homo-5-cis-13-trans prostadienoic acid        67     dl-11α,16-dihydroxy-9-oxo-16-dimethoxymethyl-                                                    dl-9β,11α,16-trihydroxy-16-formy                                    l-                                                     20-methyl-2-homo-5-cis-13-trans prostadienoic acid                                                     20-methyl-2-homo-5-cis-13-trans                                                prostadienoic acid                              68     dl-11α,16-dihydroxy-9-oxo-16-dimethoxymethyl-                                                    dl-9β,11α,16-trihydroxy-16-formy                                    l-                                                     20-ethyl-2-homo-5-cis-13-trans prostadienoic acid                                                      20-ethyl-2-homo-5-cis-13-trans                                                 prostadienoic acid                              69     nat-11α,16-dihydroxy-9-oxo-16-dimethoxymethyl-                                                   nat-9β,11α,16-trihydroxy-16-form                                    yl-                                                    20-nor-5-cis-13-trans prostadienoic acid                                                               20-nor-5-cis-13-trans prostadienoic acid        70     nat-11α,16-dihydroxy-9-oxo-16-dimethoxymethyl-                                                   nat-9β,11α,16-trihydroxy-16-form                                    yl-                                                    5-cis-13-trans prostadienoic acid                                                                      5-cis-13-trans prostadienoic acid               71     nat-11α,16-dihydroxy-9-oxo-16-dimethoxymethyl-                                                   nat-9β,11α,16-trihydroxy-16-form                                    yl-                                                    20-methyl-5-cis-13-trans prostadienoic acid                                                            20-methyl-5-cis-13-trans prostadienoic                                         acid                                            72     nat-11α,16-dihydroxy-9-oxo-16-dimethoxymethyl-                                                   nat-9β,11α,16-trihydroxy-16-form                                    yl-                                                    20-ethyl-5-cis-13-trans prostadienoic acid                                                             20-ethyl-5-cis-13-trans prostadienoic           __________________________________________________________________________                                    acid                                                   STARTING PROSTAGLANDIN  PRODUCT PROSTAGLANDIN OF                        EXAMPLE                                                                               OF THE PGE SERIES       THE 11-DEOXY PGF.sub.2β  SERIES            __________________________________________________________________________     73     dl-16-hydroxy-9-oxo-16-dimethoxymethyl-                                                                dl-9β,16-dihydroxy-16-formyl-                     20-nor-2-nor-5-cis-13-trans prostadienoic acid                                                         20-nor-2-nor-5-cis-13-trans prostadienoic                                      acid                                            74     dl-16-hydroxy-9-oxo-16-dimethoxymethyl-                                                                dl-9β,16-dihydroxy-16-formyl-                     2-nor-5-cis-13-trans prostadienoic acid                                                                2-nor-5-cis-13-trans prostadienoic acid         75     dl-16-hydroxy-9-oxo-16-dimethoxymethyl-                                                                dl-9β,16-dihydroxy-16-formyl-                     20-methyl-2-nor-5-cis-13-trans prostadienoic acid                                                      20-methyl-2-nor-5-cis-13-trans                                                 prostadienoic acid                              76     dl-16-hydroxy-9-oxo-16-dimethoxymethyl-                                                                dl-9β,16-dihydroxy-16-formyl-                     20-ethyl-2-nor-5-cis-13-trans prostadienoic acid                                                       20-ethyl-2-nor-5-cis-13-trans                                                  prostadienoic acid                              77     dl-16-hydroxy-9-oxo-16-dimethoxymethyl-                                                                dl-9β,16-dihydroxy-16-formyl-                     20-nor-5-cis-13-trans prostadienoic acid                                                               20-nor-5-cis-13-trans prostadienoic acid        78     dl-16-hydroxy-9-oxo-16-dimethoxymethyl-                                                                dl-9β,16-dihydroxy-16-formyl-                     5-cis-13-trans prostadienoic acid                                                                      5-cis-13-trans prostadienoic acid               79     dl-16-hydroxy-9-oxo-16-dimethoxymethyl-                                                                dl-9β,16-dihydroxy-16-formyl-                     20-methyl-5-cis-13-trans prostadienoic acid                                                            20-methyl-5-cis-13-trans prostadienoic                                         acid                                            80     dl-16-hydroxy-9-oxo-16-dimethoxymethyl-                                                                dl-9β,16-dihydroxy-16-formyl-                     20-ethyl-5-cis-13-trans prostadienoic acid                                                             20-ethyl-5-cis-13-trans prostadienoic                                          acid                                            81     dl-16-hydroxy-9-oxo-16-dimethoxymethyl-                                                                dl-9β,16-dihydroxy-16-formyl-                     20-nor-2-homo-5-cis-13-trans prostadienoic acid                                                        20-nor-2-homo-5-cis-13-trans prostadienoic                                     acid                                            82     dl-16-hydroxy-9-oxo-16-dimethoxymethyl-                                                                dl-9β,16-dihydroxy-16-formyl-                     2-homo-5-cis-13-trans prostadienoic acid                                                               2-homo-5-cis-13-trans prostadienoic acid        83     dl-16-hydroxy-9-oxo-16-dimethoxymethyl-                                                                dl-9β,16-dihydroxy-16-formyl-                     20-methyl-2-homo-5-cis-13-trans prostadienoic acid                                                     20-methyl-2-homo-5-cis-13-trans                                                prostadienoic acid                              84     dl-16-hydroxy-9-oxo-16-dimethoxymethyl-                                                                dl-9β,16-dihydroxy-16-formyl-                     20-ethyl-2-homo-5-cis-13-trans prostadienoic acid                                                      20-ethyl-2-homo-5-cis-13-trans                                                 prostadienoic acid                              __________________________________________________________________________

EXAMPLE 85

Treatment of the PGE₁ or PGE₂ products listed in Tables I and II will upon treatment with sodium borohydride (Example 6) or lithium perhydro-9β-borophenalylhydride (Example 7) provide the corresponding PGF₁ α and PGF₂ α compounds corresponding to the PGE₁ and PGE₂ prostaglandins of Tables I and II respectively.

While specific embodiments of this invention have been described with particularity herein, it will be understood that the invention embraces all changes and modifications of the particular compounds chosen for purposes of illustration herein which do not depart from the spirit and scope of the invention. 

What is claimed is:
 1. An optically active compound of the structure: ##STR13## wherein X is ##STR14## Y is ##STR15## R₁ is selected from the group consisting of hydrogen and hydroxyl; R₂ is selected from the group consisting of hydrogen and C₁ -C₆ alkyl;R₃ is selected from the group consisting of formyl and dimethoxymethyl; R₄ is selected from the group consisting of hydrogen and C₁ -C₃ alkyl; Z is selected from the group consisting of a divalent moiety of the formula --(CH₂)_(n), --(CH₂)_(m) OCH₂ -- and --(CH₂)_(m) SCH₂ -- wherein n is 5 to 7, and m is 3 to 5; the racemic mixture thereof, and when R₂ is hydrogen, the pharmaceutically acceptable sale thereof.
 2. The compounds according to claim 1, wherein Z is --(CH₂)₆ --.
 3. The compounds according to claim 2 wherein R₃ is formyl.
 4. The compounds according to claim 1 wherein Z is --(CH₂)_(m) SCH₂ --.
 5. The compounds according to claim 1 wherein Z is --(CH₂)_(m) OCH₂ --.
 6. The racemic compounds according to claim 3, 11α,16α/β-dihydroxy-9-oxo-16-formyl-13-trans-prostenoic acid, the individual 16α- and 16β-hydroxy racemates, and the methyl esters thereof.
 7. The optically, active compounds according to claim 3, nat. -11α,16β/β-dihydroxy-9-oxo-16-formyl-13-trans-prostenoic acid, the individual 16α- and 16β-hydroxy isomers, and the methyl esters thereof.
 8. The racemic compounds according to claim 4, 11α,16α/β-dihydroxy-9-oxo-16-formyl-3-thia-13-trans-prostenoic acid, the individual 16α- and 16β-hydroxy racemates, and the methyl esters thereof.
 9. The optically active compounds according to claim 4, nat.-11α,16α/β-dihydroxy-9-oxo-16-formyl-3-thia-13 -trans-prostenoic acid, the individual 16α- and 16β-hydroxy isomers, and the methyl esters thereof.
 10. The racemic compounds according to claim 5, 11α,16α/β-dihydroxy-9-oxo-16-formyl-3-oxa-13-trans-prostenoic acid, the individual 16α- and 16β-hydroxy racemates, and the methyl esters thereof.
 11. The optically active compounds according to claim 5, nat.-11α,16α/β-dihydroxy-9-oxo-16-formyl-3-oxa-13-trans-prostenoic acid, the individual 16α- and 16β-hydroxy isomers, and the methyl esters thereof.
 12. The racemic compounds according to claim 3, 16α/β-hydroxy-9-oxo-16-formyl-13-trans-prostenoic acid, the individual 16α- and 16β-hydroxy racemates, and the methyl esters thereof.
 13. The optically active compounds according to claim 3, nat.-16α/β-hydroxy-9-oxo-16-formyl-13-trans-prostenoic acid, the individual 16α- and 16β-hydroxy isomers, and the methyl esters thereof.
 14. The racemic compounds according to claim 4, 16α/β-hydroxy-9oxo-16-formyl-3-thia-13-trans-prostenoic acid, the individual 16α- and 16β-hydroxy racemates, and the methyl esters thereof.
 15. The optically active compounds according to claim 4, nat.-16α/β-hydroxy-9-oxo-16-formyl-3-thia-13-trans-prostenoic acid, the individual 16α- and 16β-hydroxy isomers, and the methyl esters thereof.
 16. The racemic compounds according to claim 5, 16α/β-hydroxy-9-oxo-16-formyl-3-oxa-13-trans-prostenoic acid, the individual 16α- and 16β-hydroxy racemates, and the methyl esters thereof.
 17. The optically active compounds according to claim 5, nat.-16α/β-hydroxy-9oxo-16-formyl-3-oxa-13-trans-prostenoic acid, the individual 16α- and 16β-hydroxy isomers, and the methyl esters thereof.
 18. The racemic compound according to claim 16, 11α,16α-dihydroxy-9-oxo-16-formyl-13-trans-prostenoic acid, methyl ester. 